Methods for regulating BRCA1-BRCA2-containing complex activity

ABSTRACT

The invention relates to methods of regulating the activity of at least one component of the BRCA1-BRCA2-containing complex (BRCC) by providing agents which specifically interact with BRCC components BRCC36 or BRE or nucleic acid sequences encoding BRCC36 or BRE. Methods of identifying such agents and using them to treat cancer are also provided. BRCC activities altered by such agents include ubiquitin E3 ligase activity, ubiquitin hydrolase activity, DNA repair activity, and transcriptional regulator activity.  
     BRCC36-specific antibodies and methods for diagnosing cancers associated with BRCC are also described.

INTRODUCTION

[0001] This application claims the benefit of priority from U.S. provisional applications Serial No. 60/401,433, filed on Aug. 5, 2002 and Ser. No. 60/449,950, filed on Feb. 24, 2003.

[0002] This invention was made in the course of research sponsored by the National Institute of Health (NIH Grant No. CA 90758-02). The U.S. government may have certain rights in this invention.

BACKGROUND OF THE INVENTION

[0003] Germline mutations in BRCA1 or BRCA2 genes predispose women to early onset, familial breast cancer (Hall, et al. (1990) Science 250:1684-1689; Narod, et al. (1991) Lancet 338:82-83; Miki, et al. (1994) Science 266:66-71; Wooster, et al. (1994) Science 265:2088-2090; Wooster, et al. (1995) Nature 378:789-792; Tavtigian, et al. (1996) Nat. Genet. 12:333-337). Moreover, deleterious alleles of BRCA1 and BRCA2 are responsible for almost all familial ovarian cancer, and deleterious alleles of BRCA2 are also involved in hereditary male breast cancer (Wooster, et al. (1995) Nature 378:789-792; Tavtigian, et al. (1996) Nat. Genet. 12:333-337; Easton, et al. (1993) Cancer Surv. 18:95-113; Miki, et al. (1994) Science 266:66-71).

[0004] Both BRCA1 and BRCA2 encode large proteins without extensive homology to other proteins (Miki, et al. (1994) Science 266:66-71; Tavtigian, et al. (1996) Nat. Genet. 12:333-337). The primary sequence of BRCA1 contains two motifs characteristic of transcription factors (Miki, et al. (1994) Science 266:66-71). These include a RING-finger motif and an acidic carboxyl terminus. Fusions of the carboxyl terminus to the DNA binding domain of GAL4 protein endows the chimeric protein with transcriptional stimulatory activity (Chapman and Verma (1996) Nature 382:678-679; Monteiro, et al. (1996) Proc. Natl. Acad. Sci. USA 26:13595-13599). BRCA1 may not only function as a coactivator of p53-mediated transcription (Ouchi, et al. (1998) Proc. Natl. Acad. Sci. USA 95:2302-2306; MacLachlan, et al. (2002) Mol. Cell. Biol. 22:4280-4292) but may also associate with RNA polymerase II (RNAPII) and the chromatin remodeling complex, SWI/SNF (Scully, et al. (1997) Proc. Natl. Acad. Sci. USA 94:5605-5610; Bochar, et al. (2000) Cell 102:257-265). Taken together, these observations indicate that BRCA1 may function as a transcriptional regulator.

[0005] Other reports indicate BRCA1 and BRCA2 may be involved in DNA repair. BRCA1 has been reported to interact with RAD51, BRCA2, and the RAD50 protein complex (Chen, et al. (1998) Mol. Cell 2:317-328; Zhong, et al. (1999) Science 285:747-750; Gowen, et al. (1998) Science 281:1009-1012; Scully, et al. (1997) Cell 88:265-275; Scully, et al. (1999) Mol. Cell 4:1093-1099; Sarkisian, et al. (2001) J. Biol. Chem. 276:37640-37648). BRCA1 mutant cells display sensitivity to DNA damaging agents and the BRCA1 protein has been reported to control homology-directed DNA repair (Moynahan, et al. (1999) Mol. Cell 4:511-518; Zhong, et al. (2002) J. Biol. Chem. May 30). Truncation of BRCA1 exon 11 results in defective G2-M cell cycle check point and an increased number of centrosomes (Xu, et al. (1999) Mol. Cell 3:389-395). Moreover, the BRCA2 protein interacts with RAD51 and plays a role in homology-directed repair (Wong, et al. (1997) J. Biol. Chem. 272:31941-31944; Chen, et al. (1998) Proc. Natl. Acad. Sci. USA 95:5287-5292; Mizuta, et al. (1997) Proc. Natl. Acad. Sci. USA 94:6927-6932; Marmorstein, et al. (1998) Proc. Natl. Acad. Sci. USA 95:13869-13874; Yu, et al. (2000) Genes Dev. 14:1400-1406; Moynahan, et al. (2001) Mol. Cell 7:263-272; Davies, et al. (2001) Mol. Cell 7:273-282). Furthermore, murine embryos with a targeted disruption of BRCA2 display sensitivity to ionizing radiation (Sharan, et al. (1997) Nature 386:804-810). Moreover, mouse embryo fibroblasts (MEFs) with a targeted disruption of BRCA2 exon 11 display increased sensitivity to ultraviolet light and methyl methanesulfonate (MMS) (Patel, et al. (1998) Mol. Cell 1:347-357).

[0006] BRCA1 interacts with the BRCA1-associated RING domain (BARD1) protein to form a heterodimeric complex (Wu, et al. (1996) Nat. Genet. 14:430-440; Brzovic, et al. (2001) Nat. Struct. Biol. 8:833-837). Remarkably, BARD1 association with BRCA1 potentiates the newly discovered ubiquitin E3 ligase activity of the BRCA1 protein (Hashizume, et al. (2001) J. Biol. Chem. 276:14537-14540). Detailed analysis of the BRCA1 ubiquitin E3 ligase activity has identified the RING domain of BRCA1 as the catalytic determinant for ubiquitination (Lorick, et al. (1999) Proc. Natl. Acad. Sci. USA 96:11364-11369; Hashizume, et al. (2001) J. Biol. Chem. 276:14537-14540; Ruffner, et al. (2001) Proc. Natl. Acad. Sci. USA 98:5134-5139). Furthermore, a recent report describes the ability of the BRCA1-BARD1 heterodimer to auto-ubiquitinate BRCA1 and BARD1 and trans-ubiquitinate the histone H2A(X) (Chen, et al. (2002) J. Biol. Chem. 277:22085-22092).

[0007] To date, there is no effective means of regulating the activities associated with BRCA1 or BRCA2. The present invention meets this need.

SUMMARY OF THE INVENTION

[0008] The present invention relates to methods for regulating the activity of at least one component of the BRCA1-BRCA2-containing complex (BRCC). The method involves contacting BRCC or a cell containing BRCC with an agent that interacts with a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, thereby altering an activity of BRCC.

[0009] Further provided are methods for identifying agents which modulate BRCC-associated activities. Agents are selected for the ability to alter the ubiquitin E3 ligase activity or ubiquitin hydrolase activity of BRCC as determined by changes in the level of ubiquitination of a select protein, the DNA repair activity of BRCC as determined by changes in cell survival rates upon exposure to ionizing radiation or changes in homology-directed DNA repair, or the transcriptional regulator activity of BRCC as measured by changes in the expression of genes containing p53 response elements. In addition, a method of using such agents to treat cancer is described.

[0010] Also provided are antibodies specific for BRCC36 and a method of diagnosing a cancer or risk of developing a cancer associated with BRCC.

[0011] These and other aspects of the present invention are set forth in more detail in the following description of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 shows that BRCC36 inhibits BRCA1 transcriptional regulatory activity via p53. Luciferase assays were conducted with luciferase as the reporter operably linked to an MDM2 promoter.

DETAILED DESCRIPTION OF THE INVENTION

[0013] A complex of proteins associated with BRCA2 and BRC1 have now been identified. This complex termed BRCC for BRCA1-BRCA2-containing complex contains BRCA2, BRCA1 and RAD51 as well as BRCC300, BRCC140, BRCC130, BRCC120, BRCC80, BRCC45 and BRCC36.

[0014] The present invention provides proteins encoded by the genes c6.1A (accession number S68015), referred to herein as BRCC36, and BRE (accession number NM_(—)004899). Using stable cell lines expressing epitope tagged BARD1, a multiprotein complex containing BRCA2 (SEQ ID NO:1), BRCA1 (SEQ ID NO:2), and RAD51 (SEQ ID NO:3) as well as BRCC300 (SEQ ID NO:4), BRCC140 (SEQ ID NO:5), BRCC130 (SEQ ID NO:6), BRCC120 (SEQ ID NO:7), BRCC80 (SEQ ID NO:8), BRE (SEQ ID NO:9) and BRCC36 (SEQ ID NO:10) was isolated. The complex was found to have an associated ubiquitin E3 ligase activity which was regulated by the negative regulator, BRCC36, as well as DNA repair and transcriptional regulator activities.

[0015] BRCC36 and BRE were initially isolated by identifying components that complex with BARD1. To isolate BARD1-containing complex(es), H1299- and 293-derived cell lines were developed which express FLAG®-tagged BARD1. Nuclear extract from native H1299 cells was used as the control for anti-FLAG® affinity purification. Analysis of the FLAG®-BARD1 eluate by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and silver staining revealed the specific association of BARD1 with polypeptides of 350, 300, 210, 140, 130, 120, 80, 45, 40 and 36 kDa. A combination of mass spectrometric sequencing and western blot analysis identified the 350, 210, and 40 kDa bands as BRCA2 (SEQ ID NO:1; accession number P51587), BRCA1 (SEQ ID NO:2; accession number P38398), and RAD51 (SEQ ID NO:3; accession number Q06609), respectively. This BRCA1-BRCA2-containing complex will be referred to herein as BRCC. Analysis of a number of preparations indicated that RAD51 was a substoichiometric component of BRCC. The 300, 140, 130, 120, 80, 45, and 36 kDa polypeptides corresponded to predominantly unknown proteins designated DKFZp434D193.1 (SEQ ID NO:4), FLJ21816 (SEQ ID NO:5; accession number NP_(—)078951), ubiquitin hydrolase (SEQ ID NO:6; protein FLJ23277 with accession number NP_(—)115612), BRCA1 Δ11 (SEQ ID NO:7; accession number NP_(—)009234), RAP80 (SEQ ID NO:8; accession number AAK61871); BRE (SEQ ID NO:9; Li, et al. (1995) Biochem. Biophys. Res. Commun. 206:764-74; accession number NP_(—)004890) and C6.1A (SEQ ID NO:10; Fisch, et al. (1993) Oncogene 8:3271-6; accession number P46736), respectively. Accordingly, these proteins are referred to herein as BRCC300, BRCC140, BRCC130, BRCA Δ11, BRCC80, BRE, and BRCC36, respectively.

[0016] To establish that BRCC represented a single complex and was not specific to H1299 cells, BRCC was isolated from a 293-derived cell line expressing FLAG®-BARD1. BRCC was fractionated from cell extract by anion exchange chromatography using high stringency conditions (500 mM KCl). It was found that BRCA2, BRCA1, BARD1, BRE, BRCC36 and RAD51 coelute as a large multiprotein complex, peaking in fractions 18 through 20. A small fraction of RAD51 dissociates from the complex and elutes earlier, starting at fraction 10, consistent with a modular nature for the RAD51 association with BRCC. A fraction of BRCA1 and and BARD1 eluted at a smaller molecular mass (peak fraction 16) indicating that a fraction of BRCA1/BARD1 can be resolved from the larger complex. Further, immunoprecipitation experiments using anti-BARD1 and anti-BRCA1 antibodies demonstrated the association of BRCA1, BRCA2, and BARD1 from nuclear extract of native 293 cells. Taken together, these results demonstrated the stable association of BRCA1, BRCA2, BARD1, and RAD51 in a multiprotein complex.

[0017] A 293-derived cell line stably expressing FLAG®-BRCC36 was created to demonstrate the association of the novel components of the complex with BRCA1 and BARD1. BRCC36 displayed sequence homology with the Poh1/Pad1 subunit of the 26S proteasome and subunit 5 (Jab1) of the COP9 signalosome. The homology is found in the Jab1/MPN or the JAMM domain (Verma, et al. (2002) Science 298:611-5; Cope, et al. (2002) Science 298:608-11; Yao and Cohen (2002) Nature 419:403-7). Despite its homology to Poh1 and Jab1, BRCC36 represents a distinct branch in the evolutionary tree. The BRCC36 gene was located at the Xq28 locus, a chromosomal break-point in patients with pro-lymphocytic T-cell leukaemia (Fisch, et al. (1993) supra). In two cases of pro-lymphocytic T-cell leukaemia a chromosomal break occurred in two different introns of BRCC36 (Fisch, et al. (1993) supra).

[0018] Isolation of FLAG®-BRCC36 by FLAG®-affinity purification followed by mass spectrometric sequencing and western blot analysis demonstrated the specific and stable association of BRCC36 with the other components of BRCC including BRCA2, BRCA1, BARD1 and BRE. Further, endogenous BRCC36 was detected in FLAG®-BRCC36 affinity eluate, indicating the presence of more than one BRCC36 protein per BRCC. These results demonstrate that BRCC36 and BRE are bonafide components of BRCC.

[0019] The region encoded by the exon 11 of BRCA1 is a frequent target of cancer-causing mutations. To assess the integrity of the polypeptide composition of BRCC following such cancer-causing truncations of BRCA1, a 293-derived cell line was constructed which stably expressed a truncated BRCA1 (1-509) leaving the nuclear localization signal and the Ring domain intact. To examine whether a truncation of the BARD1 protein would have a similar effect to that of BRCA1, cell lines stably expressing a truncated form of BARD1 (1-398) containing the Ring domain and nuclear localization signal were constructed. Both truncated protein complexes were purified and the resulting polypeptides were analyzed for protein composition. While truncation of BARD1 did not affect the association of any of the components of the complex, the BRCA1 truncation completely abrogated the association of BRCC36 and BRE and reduced the association of both BRCA2 and RAD51. These results demonstrate that cancer causing truncations of the BRCA1 C-terminal domain destabilize the protein composition of BRCC. However, similar C-terminal truncations of BARD1 are not deleterious to complex formation.

[0020] The interaction of the BRCC subunits were further characterized by determining whether BRCC36 directly associates with BRCA1. Six fragments spanning BRCA1 were produced in bacteria and were tested for their association with recombinant BRCC36 (Table 1). TABLE 1 BRCA1 amino acid Association Fragment residues with BRCC36 F1  1-324 − F2 260-553 − F3 502-802 + F4  758-1064 + F5 1005-1313 − F6 1314-1863 −

[0021] To determine whether the BRCA1 interaction was specific to BRCC36 and not other JAMM domain-containing proteins, the Jab1/CSN5 subunit of signalosome was also produced in recombinant form for use in the protein-protein interaction assay. While BRCC36 specifically associated with fragments 3 and 4 encoded by exon 11 of BRCA1, Jab1/CSN5 did not associate with any fragments of BRCA1 protein. These data are consistent with the results showing the loss of BRCC36 following truncations of BRCA1 exon 11.

[0022] The mRNA expression levels of BRCC36 was analyzed in various breast tumor cell lines (SK-BR-3, T47D, MCF-7 and MDA-MB-468) and breast epithelial cell lines (MCF-12F, MCF-12A and MCF-10F), breast mammary organoids (OG1 and OG2), primary breast epithelial cells, and breast tumors using real-time PCR. In general, all tissues had an increase in BRCC36 expression. Quantitative real-time PCR was employed to further analyze normal mammary ductal epithelial cells and malignant epithelial cells captured by micro-dissection. It was found that 70-80% of the sporadic mammary tumors had a 50-70% increase in BRCC36 expression levels as compared to normal tissue indicating that an increase in BRCC36 expression is indicative of breast cancer or indicative of an increased risk of developing breast cancer.

[0023] A BRCA1-BARD1 heterodimer has been described having a ubiquitin E3 ligase activity (Lorick, et al. (1999) Proc. Natl. Acad. Sci. USA 96:11364-11369; Ruffner, et al. (2001) Proc. Natl. Acad. Sci. USA 98:5134-5139; Hashizume, et al. (2001) J. Biol. Chem. 276:14537-14540). It was determined whether BRCC displayed E3 ubiquitin ligase activity and whether its enzymatic activity was similar to that of recombinant BRCA1-BARD1. Recombinant G-BRCA1/F-BARD1 was generated by co-expressing GST-tagged BRCA1(1-639) and FLAG®-tagged BARD1 in bacteria (Chen, et al. (2002) J. Biol. Chem. 277:22085-22092). Both recombinant G-BRCA1/F-BARD1 and BRCC demonstrated Ubc5-dependent ubiquitin E3 ligase activity. Of those tested (Ubc3, Ubc5A, Ubc5B, Ubc5c, UbcH7, UbcH2), Ubc5c was the most active with either recombinant G-BRCA1/F-BARD1 or the BRCC complex as the E3 enzyme. These results demonstrate that BRCC is a ubiquitin E3 ligase complex.

[0024] A close comparison of the BRCC ubiquitin ligase activity to that of recombinant G-BRCA1/F-BARD1 indicated a higher activity for recombinant G-BRCA1/F-BARD1. To further analyze this difference, the ubiquitin ligase activity of each enzyme was normalized for equal concentrations of BRCA1 and BARD1. At lower enzyme concentrations, both BRCC and G-BRCA1/F-BARD1 displayed similar E3 ubiquitin ligase activity. However, increasing concentrations of G-BRCA1/F-BARD1 resulted in higher enzyme activity while the BRCC activity reached a plateau early in the titration of the enzyme. These results indicated that the activity of BRCC may be regulated by a modulatory subunit inhibiting the enzyme at a higher enzyme/modulator concentration.

[0025] As the Jab1 subunit of the COP9 complex modulates the degradation of p27 protein (Tomoda, et al. (1999) Nature 398:160-165) and sequence similarity exits between BRCC36 and Jab1, it was determined whether BRCC36 modulated the ubiquitin ligase activity of BRCC. Accordingly, BRCC36 was expressed and purified from bacteria and analyzed for its modulation of BRCC ubiquitin ligase activity. Increasing concentrations of BRCC36 inhibited the ubiquitin ligase activity of G-BRCA1/F-BARD1 in a dose-dependent manner. Although BRCC contains BRCC36, increasing concentrations of BRCC36 also inhibited the ubiquitin ligase activity of BRCC. The inhibition of E3 ubiquitin ligase activity by BRCC36 was specific since it did not affect the ubiquitin ligase activity of another ring-containing ubiquitin ligase, the mitotic check point protein, Chfr. To rule out the possibility that the inhibition of ubiquitination is a result of a deubiquitinating activity present in the BRCC36 preparation, BRCC36 was added to the ubiquitination reaction following the formation of the ubiquitin conjugates. Although BRCC36 inhibited the ubiquitination reaction when added at the beginning of the reaction, addition of BRCC36 two hours into the ubiquitination reaction did not effect the ubiquitination reaction.

[0026] A functional and physical association of BRCA1 and BRCA2 with the p53 protein has been described (Marmorstein, et al. (1998) Proc. Natl. Acad. Sci. USA 95:13869-13874; Ouchi, et al. (1998) Proc. Natl. Acad. Sci. USA 95:2302-2306; Bochar, et al. (2000) Cell 102:257-265). Therefore, it was determined whether p53 can serve as the substrate for ubiquitination by BRCC in vitro and whether this activity could be inhibited by BRCC36. Both G-BRCA1/F-BARD1 and BRCC specifically ubiquitinated p53. Moreover, BRCC36 inhibited the ubiquitination of p53 by either G-BRCA1/F-BARD1 or BRCC. Kinetic analysis indicated that the BRCC36-mediated inhibition could not be overcome by increasing concentrations of p53, indicating a non-competitive nature of inhibition by BRCC36. Accordingly, BRCC36 functions as a specific modulator of BRCC ubiquitin ligase activity.

[0027] The inhibition of ubiquitin ligase activity of individual BRCA1 or BARD1 subunits was examined to determine whether BRCC36 directly interacts with BRCA1 or BARD1. Each protein was independently purified from bacteria as a fusion with GST and was used in a ubiquitin ligase reaction. Although recombinant G-BARD1 did not display ubiquitin ligase activity, similar concentration of G-BRCA1 exhibited modest E3 ligase activity. Increasing concentrations of G-BARD1 alone was also devoid of any activity. However, addition of G-BARD1 to G-BRCA1 potentiated the ubiquitin ligase activity of BRCA1 to levels obtained using G-BRCA1/F-BARD1 purified after coexpression of the two proteins. Furthermore, addition of increasing concentrations of BRCC36 inhibited the ubiquitin ligase activity of G-BRCA1, indicating that the two proteins may directly interact. Protein-protein interaction experiments demonstrated that BRCC36 directly and specifically interacted with both recombinant BRCA1 and recombinant BRCA1-BARD1 heterodimer. Together, these data indicate a direct interaction of BRCA1 and BRCC36 resulting in the inhibition of the BRCA1 ubiquitin E3 ligase activity.

[0028] BRCA1 mutant cells display sensitivity to DNA damaging agents, and the BRCA1 protein has been reported to control homology-directed DNA repair (Moynahan, et al. (1999) Mol. Cell 4:511-8; Zhong, et al. (2002) J. Biol. Chem. 277:28641-7). Truncation of BRCA1 exon 11 has also been shown to result in defective G2/M cell cycle checkpoint and an increased number of centrosomes (Xu, et al. (1999) Mol. Cell 3:389-95). Moreover, the BRCA2 protein interacts with RAD51 and plays a role in homology-directed repair (Sharan, et al. (1997) Nature 386:804-10; Wong, et al. (1997) J. Biol. Chem. 272:31941-4; Chen, et al. (1998) Proc. Natl. Acad. Sci. USA 95:5287-92; Mizuta, et al. (1997) Proc. Natl. Acad. Sci. USA 94:6927-32; Patel, et al. (1998) Mol. Cell 1:347-57; Marmorstein, et al. (1998) Proc. Natl. Acad. Sci. USA 95:13869-74; Yu, et al. (2000) Genes Dev. 14:1400-6; Moynahan, et al. (2001) Mol. Cell 7:263-72; Davies,. et al. (2001) Mol. Cell 7:273-82). Accordingly, the responsiveness of cell lines overexpressing BARD1 or BRCC36 to ionizing radiation was examined. FLAG®-BARD1 or FLAG®-BRCC36 cell lines were exposed to ionizing radiation (4 and 8 grays) and cellular survival was determined. Cells overexpressing BARD1 or BRCC36 exhibited opposite responsiveness following ionizing radiation. While FLAG®-BARD1 cells displayed an enhancement in cellular survival, FLAG®-BRCC36 cells showed higher sensitivity to ionizing radiation than parental 293 cells.

[0029] Further, to determine whether loss of BRCC36 and BRE resulted in DNA repair defects, HeLa cells were treated by siRNA against BRCA1, BRCC36, BRE or control siRNA and their responsiveness to ionizing radiation was measured. The experiments were performed in triplicate comparing the cells treated with siRNA against BRCC36 or BRE, to those treated with siRNA against BRCA1 and control siRNA. Treatment of cells with siRNA against BRCA1, BRCC36 and BRE resulted in decreased cell number even in the absence of ionizing radiation. However, BRCA1-, BRCC36- and BRE-depleted cells displayed a potent increased sensitivity to ionizing radiation at all doses examined.

[0030] Moreover, it was ascertained whether depletion of BRCC36 and BRE would result in disruption of the G2/M checkpoint arrest. Consistent with a defect in G2/M checkpoint, analysis of mitotic cells following 2 and 4Gy of ionizing radiation indicated that approximately three-fold more BRCC36- and BRCA1-depleted cells entered into mitosis. Depletion of BRE resulted in a more moderate defect in G2/M checkpoint arrest. Taken together these results demonstrate that BRCA1, BRCC36 and BRE are not only components of a multiprotein complex but also participate in a similar pathway of cellular responsiveness to ionizing radiation.

[0031] BRCA1 selectively coactivates p53 towards genes that direct DNA repair and cell cycle arrest (MacLachlan, et al. (2002) Mol. Cell. Biol. 22(12):4280-92). Thus, it was determined whether BRCC36 regulates the activation of p53 via BRCA1. The results indicated that BRCC36 inhibited BRCA1 transcriptional activation of p53 in a dose-dependent manner (FIG. 1).

[0032] It has now been shown that BRCA1 and BRCA2 are part of a multiprotein complex termed BRCC. A number of novel components of BRCC have been described including BRCC36 (SEQ ID NO:9), a protein with sequence homology to a subunit of the signalosome and proteasome complexes, and BRCC45/BRE (SEQ ID NO:8), a protein that is enriched in the brain and the reproductive organs. Further associated with BRCC is BRCC140 which shares homology with ubiquitin hydrolases. Detailed analysis of these new components of the complex revealed that, similar to BRCA1, depletion of BRCC36 and BRCC45/BRE resulted in increased sensitivity to ionizing radiation and loss of G2/M checkpoint arrest. Further, BRCC36 inhibits the ubiquitin E3 ligase activity and transcriptional regulator activity of BRCC and BRCC140 may function to deubiquitinate BRCC substrates. Moreover, cancer-causing truncations of BRCA1 destabilize the complex and abrogate the association of BRCC36 and BRCC45/BRE with BRCC. These findings identify BRCC, a complex containing hereditary breast cancer susceptibility genes mediating cellular responsiveness to DNA damage. Accordingly, one aspect of the present invention relates to a method of regulating the activity of at least one component of BRCC via an agent which alters the expression or activity of a BRCC36 or BRE subunit of BRCC. The method involves contacting BRCC or a cell containing BRCC with an agent that interacts with a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, so that the level of expression or activity of BRCC36 or BRE is altered thereby modulating an activity of at least one component of a BRCC. As used herein, a product of a nucleic acid sequence encoding BRCC36 or BRE is intended to include the BRCC36 or BRE mRNA transcript and BRCC36 or BRE protein.

[0033] As used herein, regulating an activity of at least one component of a BRCC is intended to include increasing or stimulating as well as decreasing or inhibiting the activity associated with a BRCC component(s). Such activities include, but are not limited to, ubiquitin E3 ligase activity, ubiquitin hydrolase activity, DNA repair activity, and transcriptional regulator activity. A change in an activity of a BRCC component(s) may be determined as exemplified herein or using other methods well-known to those of skill in the art.

[0034] It is contemplated that a change in an activity of a BRCC components by an agent which alters the expression or activity of BRCC36 or BRE may be determined using a cell-free or cell-based assay. Such assays containing BRCC are intended to include assays which encompass two or more BRCC components. BRCC components include, but are not limited to, BRCA2 (SEQ ID NO:1), BRCA1 (SEQ ID NO:2), RAD51 (SEQ ID NO:3), BRCC300 (SEQ ID NO:4), BRCC140 (SEQ ID NO:5), BRCC130 (SEQ ID NO:6), BRCA1 Δ11 (SEQ ID NO:7), BRCC80 (SEQ ID NO:8), BRE (SEQ ID NO:9), BRCC36 (SEQ ID NO:10), and BARD1 (SEQ ID NO:11). For example, an in vitro ubiquitination assay may be conducted using BRCC components BRCA1, BARD1 and BRCC36. Further, a cell-based assay for DNA repair activity may be conducted by overexpressing, for example, BARD1 or BRCC36 in a cell and determining cell survival rates upon exposure to ionizing radiation in the presence or absence of a test agent. Preferably, an assay to determine a change in an activity of a BRCC component(s) contains BRCA1, BRCA2 or BRCA1/BRCA2 in a complex with BRCC36 or BRE.

[0035] Cell-free assays of the invention may be carried out with proteins which have been recombinantly-produced or chemically-synthesized using conventional methods well-known to the skilled artisan. As will be appreciated by one of skill in the art, a full-length BRCC component protein may be produced for the assays of the invention, however, fragments of a BRCC component protein may also be used provided the fragment maintains the desired binding interaction or activity of the full-length protein (e.g., BRCA truncations of 502-802 and 758-1064). It is also contemplated that it may be desirable to produce a BRCC component protein which binds to the BRCC complex but lacks one or more activities. For example, a BRCC36 protein may be produced which binds BRCC and inhibits the ubiquitin E3 ligase activity but lacks the ability to inhibit transcriptional regulator activity of BRCC.

[0036] In general, recombinant production of a BRCC component protein may require incorporation of nucleic acid sequences encoding said protein into a recombinant expression vector in a form suitable for expression of the protein in a host cell. Exemplary nucleic acid sequences include, but are not limited to, those encoding BRCA2 (SEQ ID NO:12), BRCA1 (SEQ ID NO:13), RAD51 (SEQ ID NO:14), BRCC300 (SEQ ID NO:15), BRCC140 (SEQ ID NO:16), BRCC130 (SEQ ID NO:17), BRCA1 Δ11 (SEQ ID NO:18), BRCC80 (SEQ ID NO:19), BRE (SEQ ID NO:20), BRCC36 (SEQ ID NO:21), and BARD1 (SEQ ID NO:22). A suitable form for expression provides that the recombinant expression vector includes one or more regulatory sequences operatively-linked to the nucleic acids encoding the a BRCC component protein in a manner which allows for transcription of the nucleic acids into mRNA and translation of the mRNA into the protein. Regulatory sequences may include promoters, enhancers and other expression control elements (e.g., polyadenylation signals). Such regulatory sequences are known to those skilled in the art and are described in Goeddel D. D., ed., Gene Expression Technology, Academic Press, San Diego, Calif. (1991). It should be understood that the design of the expression vector may depend on such factors as the choice of the host cell to be transfected and/or the level of expression required. Nucleic acid sequences or expression vectors harboring nucleic acid sequences encoding a BRCC component protein may be introduced into a host cell, which may be of eukaryotic or prokaryotic origin, by standard techniques for transforming cells. Suitable methods for transforming host cells may be found in Sambrook, et al. (Molecular Cloning: A Laboratory Manual, 3rd Edition, Cold Spring Harbor Laboratory Press (2000)) and other laboratory manuals. The number of host cells transformed with a nucleic acid sequence encoding a BRCC component protein will depend, at least in part, upon the type of recombinant expression vector used and the type of transformation technique used. Nucleic acids may be introduced into a host cell transiently, or more typically, for long-term expression of a BRCC component protein the nucleic acid sequence is stably integrated into the genome of the host cell or remains as a stable episome in the host cell.

[0037] Further, nucleic acid sequences encoding a BRCC component protein may be transferred into a fertilized oocyte of a non-human animal to create a transgenic animal which expresses a BRCC component protein in one or more cell-types. A transgenic animal is an animal having cells that contain a transgene, wherein the transgene was introduced into the animal or an ancestor of the animal at a prenatal, e.g., an embryonic, stage. A transgene is a DNA which is integrated into the genome of a cell from which a transgenic animal develops and which remains in the genome of the mature animal, thereby directing the expression of an encoded gene product in one or more cell-types or tissues of the transgenic animal. Exemplary examples of non-human animals include, but are not limited to, mice, goats, sheep, pigs, cows or other domestic farm animals. Such transgenic animals are useful, for example, for large-scale production of a BRCC component protein (gene pharming) or for basic research investigations.

[0038] A transgenic non-human animal may be created, for example, by introducing a nucleic acid sequence encoding a BRCC component protein, typically linked to appropriate regulatory sequences, such as a constitutive or tissue-specific enhancer, into the male pronuclei of a fertilized oocyte, e.g., by microinjection, and allowing the oocyte to develop in a pseudopregnant female foster animal. Intron sequences and polyadenylation signals may also be included in the transgene to increase the efficiency of expression of the transgene. Methods for generating transgenic animals, particularly animals such as mice, have become conventional in the art and are described, for example, in U.S. Pat. Nos. 4,736,866 and 4,870,009. A transgenic founder animal may be used to breed additional animals carrying the transgene. Transgenic animals carrying a transgene encoding a BRCC component protein may further be bred to other transgenic animals carrying other transgenes, e.g., a transgenic animal overexpressing BRCA2 may be bred with a transgenic animal overexpressing BRCC36.

[0039] Once produced, a BRCC component protein may be recovered from culture medium or milk as a secreted polypeptide, although it also may be recovered from host cell lysates when directly expressed without a secretory signal. When a BRCC component protein is expressed in a recombinant cell other than one of human origin, the BRCC component protein is substantially free of proteins or polypeptides of human origin. However, it may be necessary to purify the BRCC component protein from recombinant cell proteins or polypeptides using conventional protein purification methods to obtain preparations that are substantially homogeneous as to the BRCC component protein.

[0040] A host cell transformed with nucleic acid sequences encoding a BRCC component protein may be used for expressing a BRCC component protein for protein production or may be used in cell-based screening assays of the invention to identify agents which modulate an activity of at least one component of BRCC. Further, a host cell transformed with nucleic acid sequences encoding a BRCC component protein may be transformed with one or more nucleic acid sequences which serve as substrates or targets of BRCC.

[0041] In a cell-based assay of the invention, one or more component of BRCC may be endogenous, overexpressed, recombinantly produced or have decreased expression. Accordingly, a cell containing BRCC, may be a cell, for example, which endogenously encodes all components of BRCC and has been transformed to overexpress a tagged BRCC36 protein. Further, it may advantageous to decrease the expression of one component. For example, expression of BRE may be blocked by gene knockout, antisense RNA, RNAi or siRNA molecules to identify agents which specifically interact with BRCC36 to modulate a cells response to ionizing radiation.

[0042] In addition to recombinant production, a BRCC component protein may be produced by direct peptide synthesis using solid-phase techniques (Merrifield J. (1963) J. Am. Chem. Soc. 85:2149-2154). Protein synthesis may be performed using manual techniques or by automation. Automated synthesis may be achieved, for example, using Applied Biosystems 431A Peptide Synthesizer (Perkin Elmer, Boston, Mass.). Various fragments of the BRCC component protein may be chemically-synthesized separately and combined using chemical methods to produce a full-length molecule.

[0043] Whether recombinantly-produced or chemically-synthesized, a BRCC component protein may be further modified for use in the assays of the invention. For example, the peptides may be glycosylated, phosphorylated or tagged (e.g., fluorescent, FLAG, and the like) using well-known methods.

[0044] Screening assays of the invention may be performed in any format that allows rapid preparation and processing of multiple reactions such as in, for example, multi-well plates of the 96-well variety. Stock solutions of the agents as well as assay components are prepared manually and all subsequent pipeting, diluting, mixing, washing, incubating, sample readout and data collecting is done using commercially available robotic pipeting equipment, automated work stations, and analytical instruments for detecting the signal generated by the assay.

[0045] In addition to components of BRCC, a variety of other reagents may be included in the screening assays. These include reagents like salts, substrates (e.g., p53 for ubiquitination assays), neutral proteins, e.g., albumin, detergents, etc. which may be used to facilitate optimal protein-protein binding and/or reduce non-specific or background interactions. Also, reagents that otherwise improve the efficiency of the assay, such as protease inhibitors, nuclease inhibitors, anti-microbial agents, and the like may be used. The mixture of components may be added in any order that provides for the requisite binding.

[0046] In a screening assay of the invention, an agent may interact with a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof (i.e., mRNA or protein), thereby increasing or decreasing expression of the BRCC36 or BRE protein or increasing or decreasing the activity of the BRCC36 or BRE protein. An activity of BRCC36 or BRE is intended to include a binding interaction with another component of BRCC as well as any enzymatic or catalytic activity of the protein. Preferably, agents will decrease, interfere with or inhibit BRCC36 gene expression or decrease, interfere with or inhibit the activity of BRCC36 protein thereby increasing BRCC activities described herein. Agents which inhibit the expression of BRCC36 or BRE may be identified using the steps of contacting a cell expressing BRCC36 or BRE protein with a test agent and monitoring or measuring the ability of the agent to inhibit or decrease the expression of BRCC36 or BRE. In such an assay, one may measure the expression levels of BRCC36 or BRE using such methods as northern blot analysis, reverse transcriptase PCR, or most preferably by operably linking the promoter or coding region of BRCC36 or BRE to a detectable marker protein such as luciferase, GFP, or β-galactosidase to more easily detect changes in expression levels of BRCC36 or BRE in the presence of a test agent.

[0047] Examples of agents which interact with nucleic acid sequences encoding BRCC36 or BRE include, but are not limited to, antisense molecules, interference RNA or ribozymes targeted to BRCC36 or BRE which inhibit the expression or small organic molecules or peptides which are capable of inhibiting expression of BRCC36 or BRE (e.g., by binding to the promoter region of the gene to inhibit transcription and subsequent expression).

[0048] Accordingly, one preferred embodiment of the present invention provides antisense, siRNA, or RNAi molecules or ribozymes targeted to nucleic acid sequences encoding BRCC36 or BRE. Using nucleic acid sequences encoding BRCC36 (SEQ ID NO:9) or BRE (SEQ ID NO:8), or homologs, analogs, or alleles thereof, one of skill in the art can readily obtain the corresponding antisense strands of the BRCC36 or BRE sequences. Such antisense sequences or biologically active fragments thereof, capable of hybridizing under stringent conditions (see, J. Sambrook et al, Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring Harbor Laboratory (1989)) to nucleic acid sequences encoding BRCC36 or BRE, would be useful in inhibiting the expression of BRCC36 or BRE protein, respectively. An example of a highly stringent hybridization condition is hybridization at 2×SSC at 65° C., followed by washing in 0.1×SSC at 65° C. for an hour. Alternatively, an exemplary highly stringent hybridization condition is in 50% formamide, 4×SSC at 42° C. Moderately high stringency conditions may also prove useful, e.g. hybridization in 4×SSC at 55° C., followed by washing in 0.1×SSC at 37° C. for an hour. An alternative exemplary moderately high stringency hybridization condition is in 50% formamide, 4×SSC at 30° C.

[0049] RNA, RNAi, siRNA and the like to decrease the expression of BRCC36 or BRE may be specific for sequences in the 5′, 3′ or middle of the mRNA encoding BRCC36 or BRE. The target region may be selected experimentally or empirically. For example, siRNA target sites in a gene of interest are selected by identifying an AA dinucleotide sequence preferably in the coding region and most preferably not near the start codon (within 75 bases) as these may be richer in regulatory protein binding sites which may interfere with binding of the siRNA. (see, e.g., Elbashir, et al. (2001) Nature 411: 494-498). The subsequent 19-27 nucleotides 3′ of the AA dinucleotide may be included in the target site and preferably have a G/C content of 30-50%. Exemplary interference RNA molecules which may be used to block the expression of BRCC36 or BRE include, but are not limited to, AA-GAGGAAGGACCGAGUAGAA (SEQ ID NO:24) and AA-GGUGCAGUACGUGAUUCAA (SEQ ID NO:25), respectively.

[0050] Other agents which inhibit expression or activity of BRCC36 or BRE may be identified by screening a library of test agents. Agents are obtained from a wide variety of sources including libraries of synthetic or natural compounds. A library may comprise either collections of pure agents or collections of agent mixtures. Examples of pure agents include, but are not limited to, peptides, polypeptides, antibodies, oligonucleotides, carbohydrates, fatty acids, steroids, purines, pyrimidines, lipids, synthetic or semi-synthetic chemicals, and purified natural products, derivatives, structural analogs or combinations thereof. Examples of agent mixtures include, but are not limited to, extracts of prokaryotic or eukaryotic cells and tissues, as well as fermentation broths and cell or tissue culture supernates. In the case of agent mixtures, one may not only identify those crude mixtures that possess the desired activity, but also monitor purification of the active component from the mixture for characterization and development as a therapeutic drug. In particular, the mixture so identified may be sequentially fractionated by methods commonly known to those skilled in the art which may include, but are not limited to, precipitation, centrifugation, filtration, ultrafiltration, selective digestion, extraction, chromatography, electrophoresis or complex formation. Each resulting subfraction may be assayed for the desired activity using the original assay until a pure, biologically active agent is obtained.

[0051] Agents of interest in the present invention are those with functional groups necessary for structural interaction with proteins, particularly hydrogen bonding, and typically include at least an amine, carbonyl, hydroxyl or carboxyl group, preferably at least two of the functional chemical groups. The agents often comprise cyclical carbon or heterocyclic structures and/or aromatic or polyaromatic structures substituted with one or more of the above functional groups.

[0052] Further, the use of replicable genetic packages, such as the bacteriophages, is one method of generating novel protein entities for regulating BRCC36 or BRE expression or activity. This method generally consists of introducing novel, exogenous DNA segments into the genome of a bacteriophage, or other amplifiable genetic package, so that the protein encoded by the non-native DNA appears on the surface of the phage. When the inserted DNA contains sequence diversity, then each recipient phage displays one variant of the template (parental) amino acid sequence encoded by the DNA, and the phage population (library) displays a vast number of different, but related, amino acid sequences.

[0053] Such techniques make it possible not only to screen a large number of potential binding molecules but make it practical to repeat the binding/elution cycles and to build secondary, biased libraries for screening analog-displaying packages that meet initial criteria.

[0054] It is well-known to those skilled in the art that it is possible to replace peptides with peptidomimetics. Peptidomimetics are generally preferable as therapeutic agents to peptides owing to their enhanced bioavailability and relative lack of attack from proteolytic enzymes. Accordingly, the present invention also provides peptidomimetics and other lead compounds which can be identified based on data obtained from structural analysis of BRCC36 or BRE. For example, peptide derivatives of a BRCC component protein which interacts with BRCC36 or BRE may be designed to modulate the interaction between BRCC36 or BRE and one or more BRCC component. A potential analog may be examined by computer modeling using a docking program such as GRAM, DOCK, or AUTODOCK. This procedure can include computer fitting of potential analogs. Computer programs can also be employed to estimate the attraction, repulsion, and steric hindrance of an analog to a potential binding site. Generally the tighter the fit (e.g., the lower the steric hindrance, and/or the greater the attractive force) the more potent the potential drug will be since these properties are consistent with a tighter binding constant. Furthermore, the more specificity in the design of a potential drug the more likely that the drug will not interfere with other properties of BRCC36 or BRE expression or activity, e.g., BRCC36 or BRE interactions which are not associated with components of BRCC. This will minimize potential side-effects due to unwanted interactions with other proteins.

[0055] Initially a potential analog could be obtained by screening a random peptide library produced by a recombinant bacteriophage, for example, or a chemical library. An analog ligand selected in this manner could be then be systematically modified by computer modeling programs until one or more promising potential ligands are identified.

[0056] Such computer modeling allows the selection of a finite number of rational chemical modifications, as opposed to the countless number of essentially random chemical modifications that could be made, and of which any one might lead to a useful drug. Thus, the three-dimensional structure and computer modeling, a large number of compounds may be rapidly screened and a few likely candidates may be determined without the laborious synthesis of untold numbers of compounds.

[0057] Once a potential peptidomimetic or lead compound is identified it can be either selected from a library of chemicals commercially available from most large chemical companies including Merck, GlaxoWelcome, Bristol-Meyers Squibb, Monsanto/Searle, Eli Lilly, Novartis and Pharmacia UpJohn, or alternatively the potential ligand is synthesized de novo. The de novo synthesis of one or even a relatively small group of specific compounds is reasonable in the art of drug design.

[0058] Agents for modulating activities associated with BRCC may also be found which act on BRCC proteins which interact with or act independent of BRCC36 or BRE. Such agents may be identified from the sources provided herein using assays for detecting the E3 ubiquitin ligase activity, ubiquitin hydrolase activity, DNA repair activity or transcriptional regulator activity of BRCC.

[0059] In a preferred embodiment, a method of identifying an agent which modulates an ubiquitin E3 ligase or ubiquitin hydrolase activity of BRCC may involve the steps of contacting BRCC with a test agent and monitoring or measuring the ability of said agent to alter the level of ubiquitination of a select protein which is indicative of ubiquitin E3 ligase activity or ubiquitin hydrolase activity of BRCC. A select protein is defined as a protein which is selectively ubiquinated or deubiquitinated by BRCC. In a preferred embodiment, a select protein is p53. The step of monitoring the ability of the agent to alter the level of ubiquitination of a select protein, such as p53 may be carried out to using an in vitro ubiquitination assay in the presence of ubiquitin (see, e.g., Hashizume, et al. (2001) J. Biol. Chem. 276:14537-14540; Chen, et al. (2002) J. Biol. Chem. 277:22085-22092) or a deubiquitination assay (see, e.g., Gewies and Grimm (2003) Cancer Res. 63(3):682-8; Strayhorn and Wadzinski (2002) Arch. Biochem. Biophys. 400(1):76-84.

[0060] In another preferred embodiment, a method of identifying an agent which modulates a DNA repair activity of BRCC may involve the steps of contacting a cell containing BRCC with a test agent and monitoring or measuring the ability of said agent to alter cell survival rates in the presence of ionizing radiation or alter homology-directed DNA repair which is indicative of DNA repair activity of BRCC. The step of monitoring the ability of the agent to alter cell survival rates may carried out using well-established methods (see, e.g., Gowen, et al. (1998) Science 281:1009-1012). Likewise, well-established methods may be used to monitor homology-directed DNA repair (see, e.g., Moynahan, et al. (1999) Mol. Cell 4:511-518). Such an assay may be conducted in vivo by measuring gene conversion repair of an introduced double-strand break. The assay may use the direct repeat-green fluorescence protein (DR-GFP) reporter, which is composed of two mutant GFP genes oriented as a direct repeat. The cleavage site for the rare cutting endonuclease I-SceI mutates one of the GFP repeats. Expression of I-SceI protein in cells that have the DR-GFP substrate integrated into their genome results in a double-strand break in the chromosome at the position of the I-SceI site. Homologous repair by gene conversion reconstructs a functional GFP+ gene. To assay the effect of an agent which inhibits DNA repair activity via homology-directed DNA repair, cells expressing I-SceI are incubated in the presence and absence of an agent and analyzed by flow cytometry either 48 or 96 hour after exposure to the agent. If the agent reduces homology-directed DNA repair activity, there will be a reduction in cell counts compared to cells not exposed to the agent.

[0061] In a further preferred embodiment, a method of identifying an agent which modulates a transcriptional regulator activity of BRCC may involve the steps of contacting a cell containing BRCC with a test agent and monitoring or measuring the ability of said agent to alter the expression of genes containing p53 response elements which is indicative of transcriptional regulator activity of BRCC. The step of monitoring the ability of the agent to alter the expression of genes containing p53 response elements may be carried out using well-known methods (see, e.g., Ouchi, et al. (1998) Proc. Natl. Acad. Sci. USA 95:2302-2306).

[0062] Other aspects of the present invention relate to agents identified as regulators or modulators of BRCC activities or as regulators or modulators of the expression or activity of BRCC36 or BRE and methods for using these agents to regulate the expression or activity of BRCC36 or BRE thereby modulating an activity of BRCC. These agents may be incorporated into a pharmaceutical composition and administered in an effective amount to a patient having cancer a cancer associated with BRCC. A cancer associated with BRCC is one which originates or is advanced by a mutation or activity of BRCC. Cancers which may be associated with BRCC include, but are not limited to, breast, ovarian, prostate, colon cancers and the like.

[0063] An effective amount of an agent which regulates or modulates the expression or activity of BRCC36 or BRE or activity of BRCC is an amount which prevents, eliminates or alleviates at least one sign or symptom of a cancer associated with BRCC. Signs or symptoms of a cancer associated with BRCC vary with the cancer being prevented or treated and are well-known to the skilled clinician. Examples of signs and/or symptoms of a cancer associated with BRCC may include, but are not limited to, tumor size, feelings of weakness, and pain perception. The amount of the agent required to achieve the desired outcome of preventing, eliminating or alleviating a sign or symptom of a cancer associated with BRCC will be dependent on the pharmaceutical composition of the agent, the patient and the condition of the patient, the mode of administration, and the type of condition or disease being prevented or treated.

[0064] Pharmaceutical compositions of the present invention comprise an effective amount of an agent which inhibits the expression or activity of BRCC36 or BRE protein or a BRCC activity and a pharmaceutically acceptable carrier. A pharmaceutically acceptable carrier is a material useful for the purpose of administering the medicament, which is preferably sterile and non-toxic, and may be solid, liquid, or gaseous materials, which is otherwise inert and medically acceptable, and is compatible with the active ingredients. A generally recognized compendium of methods and ingredients of pharmaceutical compositions is Remington: The Science and Practice of Pharmacy, Alfonso R. Gennaro, editor, 20th ed. Lippincott Williams & Wilkins: Philadelphia, Pa., 2000.

[0065] A pharmaceutical composition may contain other active ingredients such as preservatives. A pharmaceutical composition may take the form of a solution, emulsion, suspension, ointment, cream, granule, powder, drops, spray, tablet, capsule, sachet, lozenge, ampoule, pessary, or suppository. It may be administered by continuous or intermittent infusion, parenterally, intramuscularly, subcutaneously, intravenously, intra-arterially, intrathecally, intraarticularly, transdermally, orally, bucally, intranasally, as a suppository or pessary, topically, as an aerosol, spray, or drops, depending upon whether the preparation is used to treat an internal or external condition or disease. Such administration may be accompanied by pharmacologic studies to determine the optimal dose and schedule and would be within the skill of the ordinary practitioner.

[0066] A further aspect of the present invention encompasses antibodies that specifically bind to BRCC36 or BRE or homologs thereof (i.e., antibodies which bind to a single antigenic site or epitope on BRCC36 or BRE). These antibodies are useful for a variety of diagnostic purposes, e.g. diagnosing a disease or condition associated with BRCC. Furthermore, antibodies to BRCC36 or BRE may be used as antagonistic or agonist agents for regulating the activity of BRCC36 or BRE.

[0067] Antibodies to BRCC36 or BRE may be generated using methods that are well-known in the art. Such antibodies may include, but are not limited to, polyclonal, monoclonal, chimeric, single chain, Fab fragments, and fragments produced by a Fab expression library. Neutralizing antibodies are especially preferred for therapeutic use.

[0068] For the production of antibodies, various hosts including goats, rabbits, rats, mice, humans, and others, may be immunized by injection with BRCC36 or BRE or any fragment or oligopeptide thereof which has immunogenic properties. Depending on the host species, various adjuvants may be used to increase immunological response. Such adjuvants include, but are not limited to, Freund's, mineral gels such as aluminum hydroxide, and surface-active substances such as lysolecithin, pluronic polyols, polyanions, peptides, oil emulsions, keyhole limpet hemocyanin, and dinitrophenol. Among adjuvants used in humans, BCG (bacilli Calmette-Guerin) and Corynebacterium parvum are especially preferable.

[0069] It is preferred that the oligopeptides, peptides, or fragments used to induce antibodies to BRCC36 or BRE have an amino acid sequence consisting of at least five amino acids and more preferably at least 10 amino acids. It is also preferable that they are identical to a portion of the amino acid sequence of the natural protein, and they may contain the entire amino acid sequence of a small, naturally occurring molecule. Short stretches of BRCC36 or BRE amino acids may be fused with those of another protein such as keyhole limpet hemocyanin and antibody produced against the chimeric molecule.

[0070] Monoclonal antibodies to BRCC36 or BRE may be prepared using any technique which provides for the production of antibody molecules by continuous cell lines in culture. These include, but are not limited to, the hybridoma technique, the human B-cell hybridoma technique, and the EBV-hybridoma technique (Kohler, et al. (1975) Nature 256:495-497; Kozbor, et al. (1985) J. Immunol. Methods 81:31-42; Cote, et al. (1983) Proc. Natl. Acad. Sci. 80:2026-2030; Cole, et al. (1984) Mol. Cell Biol. 62:109-120).

[0071] In addition, techniques developed for the production of humanized and chimeric antibodies, the splicing of mouse antibody genes to human antibody genes to obtain a molecule with appropriate antigen specificity and biological activity may be used (Morrison, et al. (1984) Proc. Natl. Acad. Sci. 81, 6851-6855; Neuberger, et al. (1984) Nature 312:604-608; Takeda, et al. (1985) Nature 314:452-454). Alternatively, techniques described for the production of single chain antibodies may be adapted, using methods known in the art, to produce BRCC36- or BRE-specific single chain antibodies. Antibodies with related specificity, but of distinct idiotypic composition, may be generated by chain shuffling from random combinatorial immunoglobulin libraries (Burton (1991) Proc. Natl. Acad. Sci. 88,11120-11123).

[0072] Antibodies may also be produced by inducing in vivo production in the lymphocyte population or by screening immunoglobulin libraries or panels of highly specific binding reagents as is well-known in the art (Orlandi, et al. (1989) Proc. Natl. Acad. Sci. 86: 3833-3837; Winter, et al. (1991) Nature 349:293-299).

[0073] Antibody fragments, which contain specific binding sites for BRCC36 or BRE, may also be generated. For example, such fragments include, but are not limited to, the F(ab′)₂ fragments which may be produced by pepsin digestion of the antibody molecule and the Fab fragments which can be generated by reducing the disulfide bridges of the F(ab′)₂ fragments. Alternatively, Fab expression libraries may be constructed to allow rapid and easy identification of monoclonal Fab fragments with the desired specificity (Huse, et al. (1989) Science 254:1275-1281).

[0074] Further provided by the present invention are anti-idiotype antibodies (Ab2) and anti-anti-idiotype antibodies (Ab3). Ab2 are specific for the target to which anti-BRCC36 or anti-BRE antibodies of the invention bind and Ab3 are similar to BRCC36 or BRE antibodies (Ab1) in their binding specificities and biological activities (see, e.g., Wettendorff, et al., “Modulation of anti-tumor immunity by anti-idiotypic antibodies.” In: Idiotypic Network and Diseases, ed. by J. Cerny and J. Hiernaux J, Am. Soc. Microbiol., Washington D.C.: pp. 203-229, (1990)). These anti-idiotype and anti-anti-idiotype antibodies may be produced using techniques well-known to those of skill in the art. For example, an anti-idiotype antibodies (Ab2) of BRCC36 may bear the internal image of BRCC36 and bind to BRCA1 in much the same manner as BRCC36, and thus be useful for the same purposes as BRCC36.

[0075] In general, polyclonal antisera, monoclonal antibodies and other antibodies which bind to BRCC36 or BRE as the antigen (Ab1) are useful to identify epitopes of BRCC36 or BRE, to separate BRCC36 or BRE from contaminants in living tissue (e.g., in chromatographic columns and the like), and in general as research tools and as starting material essential for the development of other types of antibodies described above. Anti-idiotype antibodies (Ab2) are useful for binding BRCC and thus may be used in the treatment of cancers. The Ab3 antibodies may be useful for the same reason the Ab1 are useful. Other uses as research tools and as components for separation of BRCC36 or BRE from other contaminants of living tissue, for example, are also contemplated for the above-described antibodies.

[0076] Various immunoassays may be used for screening to identify antibodies having the desired specificity. Numerous protocols for competitive binding or immunoradiometric assays using either polyclonal or monoclonal antibodies with established specificity are well known in the art. Such immunoassays typically involve the measurement of complex formation between a specific antibody and BRCC36 or BRE. A two-site, monoclonal-based immunoassay utilizing monoclonal antibodies reactive to two non-interfering BRCC36 or BRE epitopes is preferred, but a competitive binding assay may also be employed (Maddox, supra).

[0077] Antibodies may be conjugated to a solid support suitable for a diagnostic assay (e.g., beads, plates, slides or wells formed from materials such as latex or polystyrene) in accordance with known techniques, such as precipitation. Antibodies may likewise be conjugated to detectable groups such as radiolabels (e.g., ³⁵S, ¹²⁵I, ¹³¹I), enzyme labels (e.g., horseradish peroxidase, alkaline phosphatase), and fluorescent labels (e.g., fluorescein) in accordance with known techniques.

[0078] The present invention further relates to a method for detecting or diagnosing a cancer or the risk of developing a cancer associated with BRCC. The method involves detecting the level or sequence of a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, in a sample and comparing said level or sequence of a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, in the sample to a level or sequence of a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, in a control. In accordance with the method of the invention, one or more identifiable mutations in nucleic acid sequences or proteins of BRCC36 or BRE which correlate with the presence of a BRCC associated cancer should be identified. Mutations in the nucleic acid sequence encoding BRCC36 or BRE may be readily identified using well-known methods. For example, a sample, including, but not limited to, blood or biopsy tissue, may be isolated from an individual having or suspected of having a cancer associated with BRCC and who may exhibit one or more of the typical signs or symptoms associated with the cancer. The nucleic acid sequence of BRCC36 or BRE isolated from the sample is compared to the nucleic acid sequence from a control, e.g., an individual who is known to not have a cancer associated with BRCC, to identify particular changes or mutations (e.g., deletions, insertions, conversions, or point mutations) which may result in aberrant gene expression or protein function which leads to the cancer associated with BRCC.

[0079] When detecting mutations in a nucleic acid sequence encoding BRCC36 or BRE in an individual having, suspected of having or at risk of having a BRCC associated cancer, it may be desirable to sequence the genomic locus encoding BRCC36 or BRE or PCR amplify the full-length nucleic acid sequence encoding BRCC36 or BRE or one or more sections of nucleic acid sequence encoding BRCC36 or BRE. Any suitable pair of PCR primers may be used to amplify the these nucleic acid sequence encoding BRCC36 or BRE and would be readily selected by one of skill in the art.

[0080] PCR amplification of a full-length nucleic acid sequence encoding BRCC36 or BRE or one or more sections of nucleic acid sequence encoding BRCC36 or BRE may be carried out using any standard PCR reaction reagents and conditions. Various factors such as temperature, magnesium ion concentration, DNA polymerase concentration and dNTP concentration may be considered for a suitable replication fidelity and reaction rate. Moreover, to reduce the likelihood of introducing artifactual mutations as a result of PCR amplification, a proofreading DNA polymerase such as Pho, Taq, Tth, ES4, VENT, DEEPVENT, PFUTurbo, or AmpliTaq polymerase may be used. A detailed discussion of PCR amplification is provided by Eckert, et al., in PCR: A Practical Approach, McPherson, Quirke, and Taylor, eds., IRL Press, Oxford, 1991, pp. 225-244.

[0081] PCR amplicons may be sequenced to detect mutations or analyzed by duplex formation with one or more control nucleic acid sequences encoding BRCC36 or BRE. The control may be a PCR-amplified section of the BRCC36 or BRE gene or a restriction enzyme digested fragment. Preferably, the control and the PCR-amplified section of nucleic acid sequence encoding BRCC36 or BRE isolated from the sample are similar in length and encompass the same sections of the BRCC36 or BRE gene. In general, PCR products of sections of nucleic acid sequences encoding BRCC36 or BRE from the sample are mixed with PCR products of controls and heat denatured, e.g., heating to 95° C. The mixture is then slowly cooled to allow hybridization to occur between the amplified section of BRCC36 or BRE from the sample and the control, thereby producing duplexes. Duplexes which may be produced include homoduplexes and heteroduplexes. Homoduplexes are double-stranded DNA fragments wherein the strands are fully complementary. Heteroduplexes are double-stranded DNA fragments wherein the strands are not complementary and differ by at least one base pair. If the amplified section of BRCC36 or BRE from the sample contains a mutation and is hybridized to a wild-type control, a heteroduplex will be produced. However, if the amplified section of BRCC36 or BRE from the sample contains a particular mutation which is also present in the control, a homoduplex will be produced. Likewise, an amplified section of BRCC36 or BRE from the sample lacking a mutation will form a homoduplex with a wild-type control.

[0082] When analyzing duplexes to detect mutations in nucleic acid sequences encoding BRCC36 or BRE from samples, any suitable method may be employed including, but not limited to, chemical cleavage mismatch detection (CCMD), enzymatic cleavage of mismatches (ECM), degrading gradient gel electrophoresis (DGGE), heteroduplex analysis combined with mutation detection enhancement (HAMDE) gel electrophoresis, or denaturing high performance liquid chromatography (DHPLC). Duplex analysis may also be combined with single-strand conformational polymorphism analysis (SSCP).

[0083] Mutations in BRCC36 or BRE protein sequences may also be identified by sequencing BRCC36 or BRE proteins either directly by, e.g., Edman degradation, or indirectly by antibody binding. A collection of monoclonal antibodies which specifically interact with various epitopes of wild-type BRCC36 or BRE may be used to detect sequence changes or variations (e.g., point mutations, deletions, insertions, and the like) by no longer binding to a mutated form of BRCC36 or BRE.

[0084] Further, levels of nucleic acid sequences encoding BRCC36 or BRE may be used to determine if an individual has is at risk of having a BRCC associated cancer. Levels of nucleic acid sequences encoding BRCC36 or BRE may be detected using standard methods such as northern blot analysis, RT-PCR, quantitative RT-PCR, real-time PCR, in situ hybridization and the like. Probes and primers useful for such detection methods may be readily obtained using the sequences disclosed herein. Levels of BRCC36 or BRE expression in a sample, such blood or a biopsy sample from an individual having or suspected of having a BRCC associated cancer, may be compared to levels in a control, e.g., blood or biopsy sample from an individual who does not have a cancer associated with BRCC. A change such as an increase or decrease in the levels of BRCC36 or BRE in the sample as compared to the control indicates that the individual from whom the sample was isolated may have or may be at risk at developing or having a cancer associated with BRCC.

[0085] Likewise, levels of BRCC36 or BRE protein may be determined by contacting a sample, e.g., a biopsy sample, blood sample, or other cell sample, with a selected BRCC36 or BRE antibody and measuring or detecting the level or presence of BRCC36 or BRE in the sample wherein a change in the presence or level of BRCC36 or BRE as compared to a control indicates the individual from whom the sample was taken has a cancer associated with BRCC or has an increased risk of developing a cancer associated with BRCC. A control may be blood or a biopsy sample from an individual(s) known to not have or be at risk at having a cancer associated with BRCC. As exemplified herein, an increase in BRCC36 expression is indicative of breast cancer.

[0086] For use as a diagnostic reagent, a BRCC36 or BRE antibody may optionally be labeled using diagnostic labels, such as radioactive labels, calorimetric enzyme label systems and the like conventionally used in diagnostic or therapeutic methods. The antibodies may be used to measure abnormal BRCC36 or BRE levels in selected mammalian tissue using conventional diagnostic assays, e.g., immunostaining. For example, in biopsies of tumor tissue, increases or losses in BRCC36 or BRE expression in tumor tissue could be directly verified by immunostaining.

[0087] It is further contemplated that agents which regulate the activity of BRCC300, BRCC140, BRCC130, or BRAC1 Δ11 may identified using the general methods of the invention and be useful in modulating the activity of BRCC. Moreover, antibodies directed to BRCC300, BRCC140, BRCC130, or BRCA1 Δ11 may be used for diagnosing diseases or conditions associated with BRCC.

EXAMPLE 1 Affinity-Purification of Flag-BARD1

[0088] Flag-BARD1 and a selectable marker for puromycin resistance were co-transfected into 293 human embryonic kidney cells or H1299 human lung cancer cells. Transfected cells were grown in the presence of 5 μg/ml puromycin, and individual colonies were isolated and analyzed for FLAG®-BARD1 expression. To purify the BRCC complex, nuclear extract from the FLAG®-BARD1 cell line was incubated with anti-FLAG® M2 affinity gel (SIGMA, St. Louis, Mo.). After extensive washing with buffer A (20 mM Tris-HCl pH 7.9, 0.5 M KCl, 10% glycerol, 1 mM EDTA, 5 mM DTT, 0.5% NP40), the affinity column was eluted with buffer A containing FLAG® peptide (400 μg/ml) according to manufacturer's instructions (SIGMA, St. Louis, Mo.). Other FLAG®-containing complexes were purified using a similar procedure to that described for full-length BRAD1. Analysis of BRCC on gel filtration was conducted using well-established methods (Bochar, et al. (2000) Cell 102:257-65).

EXAMPLE 2 Ionizing Radiation Treatment

[0089] Approximately 2×10⁴ cells were exposed to various doses of IR, and returned to culture for 3-4 days. Cells were trypsinized, stained with trypan blue, and numbers of live cells were counted. Each experiment included three repeats for each dosage and cell line.

EXAMPLE 3 In Vitro Ubiquitination Assays

[0090] Ubiquitination assays were conducted in a final volume of 30 μl, containing 50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 2 mM ATP, 0.6 mM dithiothreitol, 3 μg of ubiquitin, 10 ng of E1, 30 ng of the specified E2, and the indicated amount and type of E3 as specified. p53 was added as a substrate as indicated. The reactions were incubated at 37° C. for 1 hour unless otherwise indicated. Reactions were stopped with 15 μl of 5× SDS loading buffer. Samples were boiled for 3 minutes prior to SDS-PAGE analysis followed by western blot analysis.

[0091] For kinetic studies, ubiquitination reactions were setup with 10 ng of GST-BRCA1/FLAG-BARD1 and 18-30 ng of p53 as the substrate. BRCC36 (0 ng, 24 ng or 48 ng) was added for each substrate concentration. The reactions were incubated at 37° C. for 10 min followed by SDS-PAGE analysis and western blot analysis using antibodies against p53. The poly-ubiquitination products of p53 were quantified using NIH Image, and the data were subjected to a Lineweaver-Burk plot.

EXAMPLE 4 Protein Identification Using LC-MS/MS

[0092] Gel bands were excised from Colloidal Coomassie-stained gels, bands were destained, alkylated with iodoacetamide, and digested using modified Trypsin (Promega, Madison, Wis.) for 16 hours at 37° C. (Speicher, et al. (2000) J. Biomol. Tech. 11:74-86). A portion of the extracted peptides were loaded onto a nanocapillary reverse-phase 75 μm column terminating in a nanospray 15 μm tip (New Objective, Woburn, Mass.) packed with Porous R2 resin (Applied Biosystems, Foster City, Calif.). The nanocolumn was directly coupled to a Thermo Finnigan LCQ quadrupole ion trap mass spectrometer (Thermo Finnigan, San Jose, Calif.) and peptides were eluted into the mass spectrometer using an acetic acid-acetonitrile gradient. Data was acquired using triple play mode to automatically obtain peptide masses, peptide charge states, and MS/MS spectra. The resulting data were searched against the non-redundant NCBI using TurboSEQUEST Browser (Eng, et al. (1994) J. Am. Soc. Mass Spectrom. 5:976-989; Chittum, et al. (1998) Biochemistry 37:10866-10870) to identify proteins.

EXAMPLE 5 Phylogenetic Tree Analysis

[0093] Phylogenetic tree analysis of protein sequences from JAB/MPN domains (smart00232) were conducted by the Kimura distance method algorithm, using Clustalw and Phylip software (http://bioweb.pasteur.fr/). Accession numbers for the individual proteins used for the analysis are as follows: Homo sapiens C6.1A/BRCC36, accession number P46736; Mus musculus BRCC36, accession number P46737; Arabidopsis thaliana hypothetical protein, accession number AAM10390; H. sapiens PAD1/POH1, accession number AAC51866; M. musculus PAD1, accession number NP_(—)067501; Drosophila melanogaster RPN11, accession number AAF52215; A. thaliana hypothetical protein, accession number BAA7246; Caenorhabditis elegans hypothetical protein, accession number T33344; Schizosaccharomyces pombe PAD1/sks1, accession number P41878; Saccharomyces cerevisiae RPN11, accession number S56259; C. elegans hypothetical protein, accession number P41883; A. thaliana Sub5aCOP9, accession number AAL58104; A. thaliana Sub5bCOP9, accession number AAC36344; H. sapiens Jab1, accession number NP_(—)006828; M. musculus Jab1, accession number AAD03470; D. melanogaster Sub5COP9, accession number AAD28608; and S. pombe Sub5COP9, accession number NP_(—)593131.

EXAMPLE 6 Inmmunoblot Analysis

[0094] Anti-BRCA1 and anti-BRCA2 antibodies are known in the art (Bochar, et al. (2000) supra; Marmorstein, et al. (2001) Cell 104:247-257). Anti-Rad51 antibodies were commercially obtained (Upstate Biotechnology, Lake Placid, N.Y.). Anti-BRCC36 and anti-BRE antibodies were developed to peptides corresponding to the C-terminal last 20 amino acid residues of each protein. The antibodies were affinity-purified using the cognate peptide. Immunoblotting with alkaline phosphatase was performed using well-known methodologies (Bochar, et al. (2000) supra).

EXAMPLE 7 Protein Purification and Protein-Protein Interactions

[0095] Recombinant BRCA1 and BARD1 was purified as described (Chen, et al. (2002) J. Biol. Chem. 277:22085-22092). For in vitro interaction studies, whole cell extract from BL21 (GST-BRCA1 (1-639) and GST-BRCA1 fragments 1-6) and BI2J (GST-BRCA1/FLAG®-BARD1) were prepared. 5 μg of purified (His)6-FLAG®-BRCC36 protein were incubated with 400 μg of whole cell extracts or 10 μg of purified GST-BRCA1 fragment in binding buffer (20 mM Tris-HCl pH 7.9, 0.1 M KCl, 10% Glycerol, 1 mM EDTA, 2 mM MgCl 2,5 mM DTT, 0.1% NP40) for 2 hours at 4° C. with inversion. Gluthatione-sepharose beads (Pharmacia, Peapack, N.J.), previously equilibrated in binding buffer, were added to the samples and inverted for an additionnal 2 hours at 4° C. Beads were collected by centrifugation at 2000×g, 30 seconds, washed several times in binding buffer containing 500 mM KCl and 0.1% NP40 and resuspended in 2× SDS loading buffer. Proteins were resolved by SDS-PAGE and western blot analysis was performed using anti-FLAG® antibodies (SIGMA, St. Louis, Mo.).

EXAMPLE 8 Plasmid, si RNA and Transfection

[0096] BARD1 and BRCC36 were cloned in pFLAG-CMV2 (SIGMA, St. Louis, Mo.) and pCMV-5A (SIGMA, St. Louis, Mo.) vectors, respectively, by using standard PCR techniques. The siRNA molecules were artificially synthesized (Dharmacon, Inc., Lafayette, Colo.). The sequence of the BRCA1 siRNA was AA-CUUAGGUGAAGCAGCAUCU (SEQ ID NO:23); the BRCC36 siRNA was AA-GAGGAAGGACCGAGUAGAA (SEQ ID NO:24); the BRE siRNA was AA-GGUGCAGUACGUGAUUCAA (SEQ ID NO:25) and the control siRNA to transcription factor TFII-I was AA-GUUACUCAGCCAAGAACGA (SEQ ID NO:26). Transfection of the siRNA was performed with LIPOFECTAMINE™ 2000 (Life Technologies, Inc., Carlsbad, Calif.) according to the manufacturer's instructions. Briefly, cells were plated in 10-cm dish to 40% confluence. For each dish, 1.6 nmole siRNA was mixed with 20 μl LIPOFECTAMINE™ 2000 in 3 ml OPTI-MEM®. The mixture was added to cells and incubated for 6 hours. Twenty-four hours later, a second transfection was similarly performed. Cells were treated or harvested as indicated 72 hours after the initial transfection.

EXAMPLE 9 Flow Cytometric Analysis of Phosphorylated Histone H3 Staining

[0097] Seventy-two hours after siRNA transfection, cells were γ-irradiated at different dosage and then incubated at 37° C. for 1 hour before fixation in 70% ethanol. Cells were stained in 200 μl phosphate-buffered saline (PBS) containing 1% bovine serum albumin and 1 μg of polyclonal antibody against phosphorylated H3 (Upstate Biotechnology, Lake Placid, N.Y.) at 4° C. overnight, and then FITC-conjugated anti-rabbit IgG (Vector Laboratories, Inc., Burlingame, Calif.) at room temperature for 1 hour. After washing with PBS, cells were suspended in 5 μg/ml PI (SIGMA, St. Louis, Mo.), and the cellular fluorescence was measured by a flow cytometer.

1 26 1 3418 PRT Homo sapiens 1 Met Pro Ile Gly Ser Lys Glu Arg Pro Thr Phe Phe Glu Ile Phe Lys 1 5 10 15 Thr Arg Cys Asn Lys Ala Asp Leu Gly Pro Ile Ser Leu Asn Trp Phe 20 25 30 Glu Glu Leu Ser Ser Glu Ala Pro Pro Tyr Asn Ser Glu Pro Ala Glu 35 40 45 Glu Ser Glu His Lys Asn Asn Asn Tyr Glu Pro Asn Leu Phe Lys Thr 50 55 60 Pro Gln Arg Lys Pro Ser Tyr Asn Gln Leu Ala Ser Thr Pro Ile Ile 65 70 75 80 Phe Lys Glu Gln Gly Leu Thr Leu Pro Leu Tyr Gln Ser Pro Val Lys 85 90 95 Glu Leu Asp Lys Phe Lys Leu Asp Leu Gly Arg Asn Val Pro Asn Ser 100 105 110 Arg His Lys Ser Leu Arg Thr Val Lys Thr Lys Met Asp Gln Ala Asp 115 120 125 Asp Val Ser Cys Pro Leu Leu Asn Ser Cys Leu Ser Glu Ser Pro Val 130 135 140 Val Leu Gln Cys Thr His Val Thr Pro Gln Arg Asp Lys Ser Val Val 145 150 155 160 Cys Gly Ser Leu Phe His Thr Pro Lys Phe Val Lys Gly Arg Gln Thr 165 170 175 Pro Lys His Ile Ser Glu Ser Leu Gly Ala Glu Val Asp Pro Asp Met 180 185 190 Ser Trp Ser Ser Ser Leu Ala Thr Pro Pro Thr Leu Ser Ser Thr Val 195 200 205 Leu Ile Val Arg Asn Glu Glu Ala Ser Glu Thr Val Phe Pro His Asp 210 215 220 Thr Thr Ala Asn Val Lys Ser Tyr Phe Ser Asn His Asp Glu Ser Leu 225 230 235 240 Lys Lys Asn Asp Arg Phe Ile Ala Ser Val Thr Asp Ser Glu Asn Thr 245 250 255 Asn Gln Arg Glu Ala Ala Ser His Gly Phe Gly Lys Thr Ser Gly Asn 260 265 270 Ser Phe Lys Val Asn Ser Cys Lys Asp His Ile Gly Lys Ser Met Pro 275 280 285 Asn Val Leu Glu Asp Glu Val Tyr Glu Thr Val Val Asp Thr Ser Glu 290 295 300 Glu Asp Ser Phe Ser Leu Cys Phe Ser Lys Cys Arg Thr Lys Asn Leu 305 310 315 320 Gln Lys Val Arg Thr Ser Lys Thr Arg Lys Lys Ile Phe His Glu Ala 325 330 335 Asn Ala Asp Glu Cys Glu Lys Ser Lys Asn Gln Val Lys Glu Lys Tyr 340 345 350 Ser Phe Val Ser Glu Val Glu Pro Asn Asp Thr Asp Pro Leu Asp Ser 355 360 365 Asn Val Ala His Gln Lys Pro Phe Glu Ser Gly Ser Asp Lys Ile Ser 370 375 380 Lys Glu Val Val Pro Ser Leu Ala Cys Glu Trp Ser Gln Leu Thr Leu 385 390 395 400 Ser Gly Leu Asn Gly Ala Gln Met Glu Lys Ile Pro Leu Leu His Ile 405 410 415 Ser Ser Cys Asp Gln Asn Ile Ser Glu Lys Asp Leu Leu Asp Thr Glu 420 425 430 Asn Lys Arg Lys Lys Asp Phe Leu Thr Ser Glu Asn Ser Leu Pro Arg 435 440 445 Ile Ser Ser Leu Pro Lys Ser Glu Lys Pro Leu Asn Glu Glu Thr Val 450 455 460 Val Asn Lys Arg Asp Glu Glu Gln His Leu Glu Ser His Thr Asp Cys 465 470 475 480 Ile Leu Ala Val Lys Gln Ala Ile Ser Gly Thr Ser Pro Val Ala Ser 485 490 495 Ser Phe Gln Gly Ile Lys Lys Ser Ile Phe Arg Ile Arg Glu Ser Pro 500 505 510 Lys Glu Thr Phe Asn Ala Ser Phe Ser Gly His Met Thr Asp Pro Asn 515 520 525 Phe Lys Lys Glu Thr Glu Ala Ser Glu Ser Gly Leu Glu Ile His Thr 530 535 540 Val Cys Ser Gln Lys Glu Asp Ser Leu Cys Pro Asn Leu Ile Asp Asn 545 550 555 560 Gly Ser Trp Pro Ala Thr Thr Thr Gln Asn Ser Val Ala Leu Lys Asn 565 570 575 Ala Gly Leu Ile Ser Thr Leu Lys Lys Lys Thr Asn Lys Phe Ile Tyr 580 585 590 Ala Ile His Asp Glu Thr Ser Tyr Lys Gly Lys Lys Ile Pro Lys Asp 595 600 605 Gln Lys Ser Glu Leu Ile Asn Cys Ser Ala Gln Phe Glu Ala Asn Ala 610 615 620 Phe Glu Ala Pro Leu Thr Phe Ala Asn Ala Asp Ser Gly Leu Leu His 625 630 635 640 Ser Ser Val Lys Arg Ser Cys Ser Gln Asn Asp Ser Glu Glu Pro Thr 645 650 655 Leu Ser Leu Thr Ser Ser Phe Gly Thr Ile Leu Arg Lys Cys Ser Arg 660 665 670 Asn Glu Thr Cys Ser Asn Asn Thr Val Ile Ser Gln Asp Leu Asp Tyr 675 680 685 Lys Glu Ala Lys Cys Asn Lys Glu Lys Leu Gln Leu Phe Ile Thr Pro 690 695 700 Glu Ala Asp Ser Leu Ser Cys Leu Gln Glu Gly Gln Cys Glu Asn Asp 705 710 715 720 Pro Lys Ser Lys Lys Val Ser Asp Ile Lys Glu Glu Val Leu Ala Ala 725 730 735 Ala Cys His Pro Val Gln His Ser Lys Val Glu Tyr Ser Asp Thr Asp 740 745 750 Phe Gln Ser Gln Lys Ser Leu Leu Tyr Asp His Glu Asn Ala Ser Thr 755 760 765 Leu Ile Leu Thr Pro Thr Ser Lys Asp Val Leu Ser Asn Leu Val Met 770 775 780 Ile Ser Arg Gly Lys Glu Ser Tyr Lys Met Ser Asp Lys Leu Lys Gly 785 790 795 800 Asn Asn Tyr Glu Ser Asp Val Glu Leu Thr Lys Asn Ile Pro Met Glu 805 810 815 Lys Asn Gln Asp Val Cys Ala Leu Asn Glu Asn Tyr Lys Asn Val Glu 820 825 830 Leu Leu Pro Pro Glu Lys Tyr Met Arg Val Ala Ser Pro Ser Arg Lys 835 840 845 Val Gln Phe Asn Gln Asn Thr Asn Leu Arg Val Ile Gln Lys Asn Gln 850 855 860 Glu Glu Thr Thr Ser Ile Ser Lys Ile Thr Val Asn Pro Asp Ser Glu 865 870 875 880 Glu Leu Phe Ser Asp Asn Glu Asn Asn Phe Val Phe Gln Val Ala Asn 885 890 895 Glu Arg Asn Asn Leu Ala Leu Gly Asn Thr Lys Glu Leu His Glu Thr 900 905 910 Asp Leu Thr Cys Val Asn Glu Pro Ile Phe Lys Asn Ser Thr Met Val 915 920 925 Leu Tyr Gly Asp Thr Gly Asp Lys Gln Ala Thr Gln Val Ser Ile Lys 930 935 940 Lys Asp Leu Val Tyr Val Leu Ala Glu Glu Asn Lys Asn Ser Val Lys 945 950 955 960 Gln His Ile Lys Met Thr Leu Gly Gln Asp Leu Lys Ser Asp Ile Ser 965 970 975 Leu Asn Ile Asp Lys Ile Pro Glu Lys Asn Asn Asp Tyr Met Asn Lys 980 985 990 Trp Ala Gly Leu Leu Gly Pro Ile Ser Asn His Ser Phe Gly Gly Ser 995 1000 1005 Phe Arg Thr Ala Ser Asn Lys Glu Ile Lys Leu Ser Glu His Asn 1010 1015 1020 Ile Lys Lys Ser Lys Met Phe Phe Lys Asp Ile Glu Glu Gln Tyr 1025 1030 1035 Pro Thr Ser Leu Ala Cys Val Glu Ile Val Asn Thr Leu Ala Leu 1040 1045 1050 Asp Asn Gln Lys Lys Leu Ser Lys Pro Gln Ser Ile Asn Thr Val 1055 1060 1065 Ser Ala His Leu Gln Ser Ser Val Val Val Ser Asp Cys Lys Asn 1070 1075 1080 Ser His Ile Thr Pro Gln Met Leu Phe Ser Lys Gln Asp Phe Asn 1085 1090 1095 Ser Asn His Asn Leu Thr Pro Ser Gln Lys Ala Glu Ile Thr Glu 1100 1105 1110 Leu Ser Thr Ile Leu Glu Glu Ser Gly Ser Gln Phe Glu Phe Thr 1115 1120 1125 Gln Phe Arg Lys Pro Ser Tyr Ile Leu Gln Lys Ser Thr Phe Glu 1130 1135 1140 Val Pro Glu Asn Gln Met Thr Ile Leu Lys Thr Thr Ser Glu Glu 1145 1150 1155 Cys Arg Asp Ala Asp Leu His Val Ile Met Asn Ala Pro Ser Ile 1160 1165 1170 Gly Gln Val Asp Ser Ser Lys Gln Phe Glu Gly Thr Val Glu Ile 1175 1180 1185 Lys Arg Lys Phe Ala Gly Leu Leu Lys Asn Asp Cys Asn Lys Ser 1190 1195 1200 Ala Ser Gly Tyr Leu Thr Asp Glu Asn Glu Val Gly Phe Arg Gly 1205 1210 1215 Phe Tyr Ser Ala His Gly Thr Lys Leu Asn Val Ser Thr Glu Ala 1220 1225 1230 Leu Gln Lys Ala Val Lys Leu Phe Ser Asp Ile Glu Asn Ile Ser 1235 1240 1245 Glu Glu Thr Ser Ala Glu Val His Pro Ile Ser Leu Ser Ser Ser 1250 1255 1260 Lys Cys His Asp Ser Val Val Ser Met Phe Lys Ile Glu Asn His 1265 1270 1275 Asn Asp Lys Thr Val Ser Glu Lys Asn Asn Lys Cys Gln Leu Ile 1280 1285 1290 Leu Gln Asn Asn Ile Glu Met Thr Thr Gly Thr Phe Val Glu Glu 1295 1300 1305 Ile Thr Glu Asn Tyr Lys Arg Asn Thr Glu Asn Glu Asp Asn Lys 1310 1315 1320 Tyr Thr Ala Ala Ser Arg Asn Ser His Asn Leu Glu Phe Asp Gly 1325 1330 1335 Ser Asp Ser Ser Lys Asn Asp Thr Val Cys Ile His Lys Asp Glu 1340 1345 1350 Thr Asp Leu Leu Phe Thr Asp Gln His Asn Ile Cys Leu Lys Leu 1355 1360 1365 Ser Gly Gln Phe Met Lys Glu Gly Asn Thr Gln Ile Lys Glu Asp 1370 1375 1380 Leu Ser Asp Leu Thr Phe Leu Glu Val Ala Lys Ala Gln Glu Ala 1385 1390 1395 Cys His Gly Asn Thr Ser Asn Lys Glu Gln Leu Thr Ala Thr Lys 1400 1405 1410 Thr Glu Gln Asn Ile Lys Asp Phe Glu Thr Ser Asp Thr Phe Phe 1415 1420 1425 Gln Thr Ala Ser Gly Lys Asn Ile Ser Val Ala Lys Glu Ser Phe 1430 1435 1440 Asn Lys Ile Val Asn Phe Phe Asp Gln Lys Pro Glu Glu Leu His 1445 1450 1455 Asn Phe Ser Leu Asn Ser Glu Leu His Ser Asp Ile Arg Lys Asn 1460 1465 1470 Lys Met Asp Ile Leu Ser Tyr Glu Glu Thr Asp Ile Val Lys His 1475 1480 1485 Lys Ile Leu Lys Glu Ser Val Pro Val Gly Thr Gly Asn Gln Leu 1490 1495 1500 Val Thr Phe Gln Gly Gln Pro Glu Arg Asp Glu Lys Ile Lys Glu 1505 1510 1515 Pro Thr Leu Leu Gly Phe His Thr Ala Ser Gly Lys Lys Val Lys 1520 1525 1530 Ile Ala Lys Glu Ser Leu Asp Lys Val Lys Asn Leu Phe Asp Glu 1535 1540 1545 Lys Glu Gln Gly Thr Ser Glu Ile Thr Ser Phe Ser His Gln Trp 1550 1555 1560 Ala Lys Thr Leu Lys Tyr Arg Glu Ala Cys Lys Asp Leu Glu Leu 1565 1570 1575 Ala Cys Glu Thr Ile Glu Ile Thr Ala Ala Pro Lys Cys Lys Glu 1580 1585 1590 Met Gln Asn Ser Leu Asn Asn Asp Lys Asn Leu Val Ser Ile Glu 1595 1600 1605 Thr Val Val Pro Pro Lys Leu Leu Ser Asp Asn Leu Cys Arg Gln 1610 1615 1620 Thr Glu Asn Leu Lys Thr Ser Lys Ser Ile Phe Leu Lys Val Lys 1625 1630 1635 Val His Glu Asn Val Glu Lys Glu Thr Ala Lys Ser Pro Ala Thr 1640 1645 1650 Cys Tyr Thr Asn Gln Ser Pro Tyr Ser Val Ile Glu Asn Ser Ala 1655 1660 1665 Leu Ala Phe Tyr Thr Ser Cys Ser Arg Lys Thr Ser Val Ser Gln 1670 1675 1680 Thr Ser Leu Leu Glu Ala Lys Lys Trp Leu Arg Glu Gly Ile Phe 1685 1690 1695 Asp Gly Gln Pro Glu Arg Ile Asn Thr Ala Asp Tyr Val Gly Asn 1700 1705 1710 Tyr Leu Tyr Glu Asn Asn Ser Asn Ser Thr Ile Ala Glu Asn Asp 1715 1720 1725 Lys Asn His Leu Ser Glu Lys Gln Asp Thr Tyr Leu Ser Asn Ser 1730 1735 1740 Ser Met Ser Asn Ser Tyr Ser Tyr His Ser Asp Glu Val Tyr Asn 1745 1750 1755 Asp Ser Gly Tyr Leu Ser Lys Asn Lys Leu Asp Ser Gly Ile Glu 1760 1765 1770 Pro Val Leu Lys Asn Val Glu Asp Gln Lys Asn Thr Ser Phe Ser 1775 1780 1785 Lys Val Ile Ser Asn Val Lys Asp Ala Asn Ala Tyr Pro Gln Thr 1790 1795 1800 Val Asn Glu Asp Ile Cys Val Glu Glu Leu Val Thr Ser Ser Ser 1805 1810 1815 Pro Cys Lys Asn Lys Asn Ala Ala Ile Lys Leu Ser Ile Ser Asn 1820 1825 1830 Ser Asn Asn Phe Glu Val Gly Pro Pro Ala Phe Arg Ile Ala Ser 1835 1840 1845 Gly Lys Ile Val Cys Val Ser His Glu Thr Ile Lys Lys Val Lys 1850 1855 1860 Asp Ile Phe Thr Asp Ser Phe Ser Lys Val Ile Lys Glu Asn Asn 1865 1870 1875 Glu Asn Lys Ser Lys Ile Cys Gln Thr Lys Ile Met Ala Gly Cys 1880 1885 1890 Tyr Glu Ala Leu Asp Asp Ser Glu Asp Ile Leu His Asn Ser Leu 1895 1900 1905 Asp Asn Asp Glu Cys Ser Thr His Ser His Lys Val Phe Ala Asp 1910 1915 1920 Ile Gln Ser Glu Glu Ile Leu Gln His Asn Gln Asn Met Ser Gly 1925 1930 1935 Leu Glu Lys Val Ser Lys Ile Ser Pro Cys Asp Val Ser Leu Glu 1940 1945 1950 Thr Ser Asp Ile Cys Lys Cys Ser Ile Gly Lys Leu His Lys Ser 1955 1960 1965 Val Ser Ser Ala Asn Thr Cys Gly Ile Phe Ser Thr Ala Ser Gly 1970 1975 1980 Lys Ser Val Gln Val Ser Asp Ala Ser Leu Gln Asn Ala Arg Gln 1985 1990 1995 Val Phe Ser Glu Ile Glu Asp Ser Thr Lys Gln Val Phe Ser Lys 2000 2005 2010 Val Leu Phe Lys Ser Asn Glu His Ser Asp Gln Leu Thr Arg Glu 2015 2020 2025 Glu Asn Thr Ala Ile Arg Thr Pro Glu His Leu Ile Ser Gln Lys 2030 2035 2040 Gly Phe Ser Tyr Asn Val Val Asn Ser Ser Ala Phe Ser Gly Phe 2045 2050 2055 Ser Thr Ala Ser Gly Lys Gln Val Ser Ile Leu Glu Ser Ser Leu 2060 2065 2070 His Lys Val Lys Gly Val Leu Glu Glu Phe Asp Leu Ile Arg Thr 2075 2080 2085 Glu His Ser Leu His Tyr Ser Pro Thr Ser Arg Gln Asn Val Ser 2090 2095 2100 Lys Ile Leu Pro Arg Val Asp Lys Arg Asn Pro Glu His Cys Val 2105 2110 2115 Asn Ser Glu Met Glu Lys Thr Cys Ser Lys Glu Phe Lys Leu Ser 2120 2125 2130 Asn Asn Leu Asn Val Glu Gly Gly Ser Ser Glu Asn Asn His Ser 2135 2140 2145 Ile Lys Val Ser Pro Tyr Leu Ser Gln Phe Gln Gln Asp Lys Gln 2150 2155 2160 Gln Leu Val Leu Gly Thr Lys Val Ser Leu Val Glu Asn Ile His 2165 2170 2175 Val Leu Gly Lys Glu Gln Ala Ser Pro Lys Asn Val Lys Met Glu 2180 2185 2190 Ile Gly Lys Thr Glu Thr Phe Ser Asp Val Pro Val Lys Thr Asn 2195 2200 2205 Ile Glu Val Cys Ser Thr Tyr Ser Lys Asp Ser Glu Asn Tyr Phe 2210 2215 2220 Glu Thr Glu Ala Val Glu Ile Ala Lys Ala Phe Met Glu Asp Asp 2225 2230 2235 Glu Leu Thr Asp Ser Lys Leu Pro Ser His Ala Thr His Ser Leu 2240 2245 2250 Phe Thr Cys Pro Glu Asn Glu Glu Met Val Leu Ser Asn Ser Arg 2255 2260 2265 Ile Gly Lys Arg Arg Gly Glu Pro Leu Ile Leu Val Gly Glu Pro 2270 2275 2280 Ser Ile Lys Arg Asn Leu Leu Asn Glu Phe Asp Arg Ile Ile Glu 2285 2290 2295 Asn Gln Glu Lys Ser Leu Lys Ala Ser Lys Ser Thr Pro Asp Gly 2300 2305 2310 Thr Ile Lys Asp Arg Arg Leu Phe Met His His Val Ser Leu Glu 2315 2320 2325 Pro Ile Thr Cys Val Pro Phe Arg Thr Thr Lys Glu Arg Gln Glu 2330 2335 2340 Ile Gln Asn Pro Asn Phe Thr Ala Pro Gly Gln Glu Phe Leu Ser 2345 2350 2355 Lys Ser His Leu Tyr Glu His Leu Thr Leu Glu Lys Ser Ser Ser 2360 2365 2370 Asn Leu Ala Val Ser Gly His Pro Phe Tyr Gln Val Ser Ala Thr 2375 2380 2385 Arg Asn Glu Lys Met Arg His Leu Ile Thr Thr Gly Arg Pro Thr 2390 2395 2400 Lys Val Phe Val Pro Pro Phe Lys Thr Lys Ser His Phe His Arg 2405 2410 2415 Val Glu Gln Cys Val Arg Asn Ile Asn Leu Glu Glu Asn Arg Gln 2420 2425 2430 Lys Gln Asn Ile Asp Gly His Gly Ser Asp Asp Ser Lys Asn Lys 2435 2440 2445 Ile Asn Asp Asn Glu Ile His Gln Phe Asn Lys Asn Asn Ser Asn 2450 2455 2460 Gln Ala Ala Ala Val Thr Phe Thr Lys Cys Glu Glu Glu Pro Leu 2465 2470 2475 Asp Leu Ile Thr Ser Leu Gln Asn Ala Arg Asp Ile Gln Asp Met 2480 2485 2490 Arg Ile Lys Lys Lys Gln Arg Gln Arg Val Phe Pro Gln Pro Gly 2495 2500 2505 Ser Leu Tyr Leu Ala Lys Thr Ser Thr Leu Pro Arg Ile Ser Leu 2510 2515 2520 Lys Ala Ala Val Gly Gly Gln Val Pro Ser Ala Cys Ser His Lys 2525 2530 2535 Gln Leu Tyr Thr Tyr Gly Val Ser Lys His Cys Ile Lys Ile Asn 2540 2545 2550 Ser Lys Asn Ala Glu Ser Phe Gln Phe His Thr Glu Asp Tyr Phe 2555 2560 2565 Gly Lys Glu Ser Leu Trp Thr Gly Lys Gly Ile Gln Leu Ala Asp 2570 2575 2580 Gly Gly Trp Leu Ile Pro Ser Asn Asp Gly Lys Ala Gly Lys Glu 2585 2590 2595 Glu Phe Tyr Arg Ala Leu Cys Asp Thr Pro Gly Val Asp Pro Lys 2600 2605 2610 Leu Ile Ser Arg Ile Trp Val Tyr Asn His Tyr Arg Trp Ile Ile 2615 2620 2625 Trp Lys Leu Ala Ala Met Glu Cys Ala Phe Pro Lys Glu Phe Ala 2630 2635 2640 Asn Arg Cys Leu Ser Pro Glu Arg Val Leu Leu Gln Leu Lys Tyr 2645 2650 2655 Arg Tyr Asp Thr Glu Ile Asp Arg Ser Arg Arg Ser Ala Ile Lys 2660 2665 2670 Lys Ile Met Glu Arg Asp Asp Thr Ala Ala Lys Thr Leu Val Leu 2675 2680 2685 Cys Val Ser Asp Ile Ile Ser Leu Ser Ala Asn Ile Ser Glu Thr 2690 2695 2700 Ser Ser Asn Lys Thr Ser Ser Ala Asp Thr Gln Lys Val Ala Ile 2705 2710 2715 Ile Glu Leu Thr Asp Gly Trp Tyr Ala Val Lys Ala Gln Leu Asp 2720 2725 2730 Pro Pro Leu Leu Ala Val Leu Lys Asn Gly Arg Leu Thr Val Gly 2735 2740 2745 Gln Lys Ile Ile Leu His Gly Ala Glu Leu Val Gly Ser Pro Asp 2750 2755 2760 Ala Cys Thr Pro Leu Glu Ala Pro Glu Ser Leu Met Leu Lys Ile 2765 2770 2775 Ser Ala Asn Ser Thr Arg Pro Ala Arg Trp Tyr Thr Lys Leu Gly 2780 2785 2790 Phe Phe Pro Asp Pro Arg Pro Phe Pro Leu Pro Leu Ser Ser Leu 2795 2800 2805 Phe Ser Asp Gly Gly Asn Val Gly Cys Val Asp Val Ile Ile Gln 2810 2815 2820 Arg Ala Tyr Pro Ile Gln Trp Met Glu Lys Thr Ser Ser Gly Leu 2825 2830 2835 Tyr Ile Phe Arg Asn Glu Arg Glu Glu Glu Lys Glu Ala Ala Lys 2840 2845 2850 Tyr Val Glu Ala Gln Gln Lys Arg Leu Glu Ala Leu Phe Thr Lys 2855 2860 2865 Ile Gln Glu Glu Phe Glu Glu His Glu Glu Asn Thr Thr Lys Pro 2870 2875 2880 Tyr Leu Pro Ser Arg Ala Leu Thr Arg Gln Gln Val Arg Ala Leu 2885 2890 2895 Gln Asp Gly Ala Glu Leu Tyr Glu Ala Val Lys Asn Ala Ala Asp 2900 2905 2910 Pro Ala Tyr Leu Glu Gly Tyr Phe Ser Glu Glu Gln Leu Arg Ala 2915 2920 2925 Leu Asn Asn His Arg Gln Met Leu Asn Asp Lys Lys Gln Ala Gln 2930 2935 2940 Ile Gln Leu Glu Ile Arg Lys Ala Met Glu Ser Ala Glu Gln Lys 2945 2950 2955 Glu Gln Gly Leu Ser Arg Asp Val Thr Thr Val Trp Lys Leu Arg 2960 2965 2970 Ile Val Ser Tyr Ser Lys Lys Glu Lys Asp Ser Val Ile Leu Ser 2975 2980 2985 Ile Trp Arg Pro Ser Ser Asp Leu Tyr Ser Leu Leu Thr Glu Gly 2990 2995 3000 Lys Arg Tyr Arg Ile Tyr His Leu Ala Thr Ser Lys Ser Lys Ser 3005 3010 3015 Lys Ser Glu Arg Ala Asn Ile Gln Leu Ala Ala Thr Lys Lys Thr 3020 3025 3030 Gln Tyr Gln Gln Leu Pro Val Ser Asp Glu Ile Leu Phe Gln Ile 3035 3040 3045 Tyr Gln Pro Arg Glu Pro Leu His Phe Ser Lys Phe Leu Asp Pro 3050 3055 3060 Asp Phe Gln Pro Ser Cys Ser Glu Val Asp Leu Ile Gly Phe Val 3065 3070 3075 Val Ser Val Val Lys Lys Thr Gly Leu Ala Pro Phe Val Tyr Leu 3080 3085 3090 Ser Asp Glu Cys Tyr Asn Leu Leu Ala Ile Lys Phe Trp Ile Asp 3095 3100 3105 Leu Asn Glu Asp Ile Ile Lys Pro His Met Leu Ile Ala Ala Ser 3110 3115 3120 Asn Leu Gln Trp Arg Pro Glu Ser Lys Ser Gly Leu Leu Thr Leu 3125 3130 3135 Phe Ala Gly Asp Phe Ser Val Phe Ser Ala Ser Pro Lys Glu Gly 3140 3145 3150 His Phe Gln Glu Thr Phe Asn Lys Met Lys Asn Thr Val Glu Asn 3155 3160 3165 Ile Asp Ile Leu Cys Asn Glu Ala Glu Asn Lys Leu Met His Ile 3170 3175 3180 Leu His Ala Asn Asp Pro Lys Trp Ser Thr Pro Thr Lys Asp Cys 3185 3190 3195 Thr Ser Gly Pro Tyr Thr Ala Gln Ile Ile Pro Gly Thr Gly Asn 3200 3205 3210 Lys Leu Leu Met Ser Ser Pro Asn Cys Glu Ile Tyr Tyr Gln Ser 3215 3220 3225 Pro Leu Ser Leu Cys Met Ala Lys Arg Lys Ser Val Ser Thr Pro 3230 3235 3240 Val Ser Ala Gln Met Thr Ser Lys Ser Cys Lys Gly Glu Lys Glu 3245 3250 3255 Ile Asp Asp Gln Lys Asn Cys Lys Lys Arg Arg Ala Leu Asp Phe 3260 3265 3270 Leu Ser Arg Leu Pro Leu Pro Pro Pro Val Ser Pro Ile Cys Thr 3275 3280 3285 Phe Val Ser Pro Ala Ala Gln Lys Ala Phe Gln Pro Pro Arg Ser 3290 3295 3300 Cys Gly Thr Lys Tyr Glu Thr Pro Ile Lys Lys Lys Glu Leu Asn 3305 3310 3315 Ser Pro Gln Met Thr Pro Phe Lys Lys Phe Asn Glu Ile Ser Leu 3320 3325 3330 Leu Glu Ser Asn Ser Ile Ala Asp Glu Glu Leu Ala Leu Ile Asn 3335 3340 3345 Thr Gln Ala Leu Leu Ser Gly Ser Thr Gly Glu Lys Gln Phe Ile 3350 3355 3360 Ser Val Ser Glu Ser Thr Arg Thr Ala Pro Thr Ser Ser Glu Asp 3365 3370 3375 Tyr Leu Arg Leu Lys Arg Arg Cys Thr Thr Ser Leu Ile Lys Glu 3380 3385 3390 Gln Glu Ser Ser Gln Ala Ser Thr Glu Glu Cys Glu Lys Asn Lys 3395 3400 3405 Gln Asp Thr Ile Thr Thr Lys Lys Tyr Ile 3410 3415 2 1863 PRT Homo sapiens 2 Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gln Asn Val Ile Asn 1 5 10 15 Ala Met Gln Lys Ile Leu Glu Cys Pro Ile Cys Leu Glu Leu Ile Lys 20 25 30 Glu Pro Val Ser Thr Lys Cys Asp His Ile Phe Cys Lys Phe Cys Met 35 40 45 Leu Lys Leu Leu Asn Gln Lys Lys Gly Pro Ser Gln Cys Pro Leu Cys 50 55 60 Lys Asn Asp Ile Thr Lys Arg Ser Leu Gln Glu Ser Thr Arg Phe Ser 65 70 75 80 Gln Leu Val Glu Glu Leu Leu Lys Ile Ile Cys Ala Phe Gln Leu Asp 85 90 95 Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn 100 105 110 Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser Ile Ile Gln Ser Met 115 120 125 Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gln Ser Glu Pro Glu Asn 130 135 140 Pro Ser Leu Gln Glu Thr Ser Leu Ser Val Gln Leu Ser Asn Leu Gly 145 150 155 160 Thr Val Arg Thr Leu Arg Thr Lys Gln Arg Ile Gln Pro Gln Lys Thr 165 170 175 Ser Val Tyr Ile Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn 180 185 190 Lys Ala Thr Tyr Cys Ser Val Gly Asp Gln Glu Leu Leu Gln Ile Thr 195 200 205 Pro Gln Gly Thr Arg Asp Glu Ile Ser Leu Asp Ser Ala Lys Lys Ala 210 215 220 Ala Cys Glu Phe Ser Glu Thr Asp Val Thr Asn Thr Glu His His Gln 225 230 235 240 Pro Ser Asn Asn Asp Leu Asn Thr Thr Glu Lys Arg Ala Ala Glu Arg 245 250 255 His Pro Glu Lys Tyr Gln Gly Ser Ser Val Ser Asn Leu His Val Glu 260 265 270 Pro Cys Gly Thr Asn Thr His Ala Ser Ser Leu Gln His Glu Asn Ser 275 280 285 Ser Leu Leu Leu Thr Lys Asp Arg Met Asn Val Glu Lys Ala Glu Phe 290 295 300 Cys Asn Lys Ser Lys Gln Pro Gly Leu Ala Arg Ser Gln His Asn Arg 305 310 315 320 Trp Ala Gly Ser Lys Glu Thr Cys Asn Asp Arg Arg Thr Pro Ser Thr 325 330 335 Glu Lys Lys Val Asp Leu Asn Ala Asp Pro Leu Cys Glu Arg Lys Glu 340 345 350 Trp Asn Lys Gln Lys Leu Pro Cys Ser Glu Asn Pro Arg Asp Thr Glu 355 360 365 Asp Val Pro Trp Ile Thr Leu Asn Ser Ser Ile Gln Lys Val Asn Glu 370 375 380 Trp Phe Ser Arg Ser Asp Glu Leu Leu Gly Ser Asp Asp Ser His Asp 385 390 395 400 Gly Glu Ser Glu Ser Asn Ala Lys Val Ala Asp Val Leu Asp Val Leu 405 410 415 Asn Glu Val Asp Glu Tyr Ser Gly Ser Ser Glu Lys Ile Asp Leu Leu 420 425 430 Ala Ser Asp Pro His Glu Ala Leu Ile Cys Lys Ser Glu Arg Val His 435 440 445 Ser Lys Ser Val Glu Ser Asn Ile Glu Asp Lys Ile Phe Gly Lys Thr 450 455 460 Tyr Arg Lys Lys Ala Ser Leu Pro Asn Leu Ser His Val Thr Glu Asn 465 470 475 480 Leu Ile Ile Gly Ala Phe Val Thr Glu Pro Gln Ile Ile Gln Glu Arg 485 490 495 Pro Leu Thr Asn Lys Leu Lys Arg Lys Arg Arg Pro Thr Ser Gly Leu 500 505 510 His Pro Glu Asp Phe Ile Lys Lys Ala Asp Leu Ala Val Gln Lys Thr 515 520 525 Pro Glu Met Ile Asn Gln Gly Thr Asn Gln Thr Glu Gln Asn Gly Gln 530 535 540 Val Met Asn Ile Thr Asn Ser Gly His Glu Asn Lys Thr Lys Gly Asp 545 550 555 560 Ser Ile Gln Asn Glu Lys Asn Pro Asn Pro Ile Glu Ser Leu Glu Lys 565 570 575 Glu Ser Ala Phe Lys Thr Lys Ala Glu Pro Ile Ser Ser Ser Ile Ser 580 585 590 Asn Met Glu Leu Glu Leu Asn Ile His Asn Ser Lys Ala Pro Lys Lys 595 600 605 Asn Arg Leu Arg Arg Lys Ser Ser Thr Arg His Ile His Ala Leu Glu 610 615 620 Leu Val Val Ser Arg Asn Leu Ser Pro Pro Asn Cys Thr Glu Leu Gln 625 630 635 640 Ile Asp Ser Cys Ser Ser Ser Glu Glu Ile Lys Lys Lys Lys Tyr Asn 645 650 655 Gln Met Pro Val Arg His Ser Arg Asn Leu Gln Leu Met Glu Gly Lys 660 665 670 Glu Pro Ala Thr Gly Ala Lys Lys Ser Asn Lys Pro Asn Glu Gln Thr 675 680 685 Ser Lys Arg His Asp Ser Asp Thr Phe Pro Glu Leu Lys Leu Thr Asn 690 695 700 Ala Pro Gly Ser Phe Thr Lys Cys Ser Asn Thr Ser Glu Leu Lys Glu 705 710 715 720 Phe Val Asn Pro Ser Leu Pro Arg Glu Glu Lys Glu Glu Lys Leu Glu 725 730 735 Thr Val Lys Val Ser Asn Asn Ala Glu Asp Pro Lys Asp Leu Met Leu 740 745 750 Ser Gly Glu Arg Val Leu Gln Thr Glu Arg Ser Val Glu Ser Ser Ser 755 760 765 Ile Ser Leu Val Pro Gly Thr Asp Tyr Gly Thr Gln Glu Ser Ile Ser 770 775 780 Leu Leu Glu Val Ser Thr Leu Gly Lys Ala Lys Thr Glu Pro Asn Lys 785 790 795 800 Cys Val Ser Gln Cys Ala Ala Phe Glu Asn Pro Lys Gly Leu Ile His 805 810 815 Gly Cys Ser Lys Asp Asn Arg Asn Asp Thr Glu Gly Phe Lys Tyr Pro 820 825 830 Leu Gly His Glu Val Asn His Ser Arg Glu Thr Ser Ile Glu Met Glu 835 840 845 Glu Ser Glu Leu Asp Ala Gln Tyr Leu Gln Asn Thr Phe Lys Val Ser 850 855 860 Lys Arg Gln Ser Phe Ala Pro Phe Ser Asn Pro Gly Asn Ala Glu Glu 865 870 875 880 Glu Cys Ala Thr Phe Ser Ala His Ser Gly Ser Leu Lys Lys Gln Ser 885 890 895 Pro Lys Val Thr Phe Glu Cys Glu Gln Lys Glu Glu Asn Gln Gly Lys 900 905 910 Asn Glu Ser Asn Ile Lys Pro Val Gln Thr Val Asn Ile Thr Ala Gly 915 920 925 Phe Pro Val Val Gly Gln Lys Asp Lys Pro Val Asp Asn Ala Lys Cys 930 935 940 Ser Ile Lys Gly Gly Ser Arg Phe Cys Leu Ser Ser Gln Phe Arg Gly 945 950 955 960 Asn Glu Thr Gly Leu Ile Thr Pro Asn Lys His Gly Leu Leu Gln Asn 965 970 975 Pro Tyr Arg Ile Pro Pro Leu Phe Pro Ile Lys Ser Phe Val Lys Thr 980 985 990 Lys Cys Lys Lys Asn Leu Leu Glu Glu Asn Phe Glu Glu His Ser Met 995 1000 1005 Ser Pro Glu Arg Glu Met Gly Asn Glu Asn Ile Pro Ser Thr Val 1010 1015 1020 Ser Thr Ile Ser Arg Asn Asn Ile Arg Glu Asn Val Phe Lys Glu 1025 1030 1035 Ala Ser Ser Ser Asn Ile Asn Glu Val Gly Ser Ser Thr Asn Glu 1040 1045 1050 Val Gly Ser Ser Ile Asn Glu Ile Gly Ser Ser Asp Glu Asn Ile 1055 1060 1065 Gln Ala Glu Leu Gly Arg Asn Arg Gly Pro Lys Leu Asn Ala Met 1070 1075 1080 Leu Arg Leu Gly Val Leu Gln Pro Glu Val Tyr Lys Gln Ser Leu 1085 1090 1095 Pro Gly Ser Asn Cys Lys His Pro Glu Ile Lys Lys Gln Glu Tyr 1100 1105 1110 Glu Glu Val Val Gln Thr Val Asn Thr Asp Phe Ser Pro Tyr Leu 1115 1120 1125 Ile Ser Asp Asn Leu Glu Gln Pro Met Gly Ser Ser His Ala Ser 1130 1135 1140 Gln Val Cys Ser Glu Thr Pro Asp Asp Leu Leu Asp Asp Gly Glu 1145 1150 1155 Ile Lys Glu Asp Thr Ser Phe Ala Glu Asn Asp Ile Lys Glu Ser 1160 1165 1170 Ser Ala Val Phe Ser Lys Ser Val Gln Lys Gly Glu Leu Ser Arg 1175 1180 1185 Ser Pro Ser Pro Phe Thr His Thr His Leu Ala Gln Gly Tyr Arg 1190 1195 1200 Arg Gly Ala Lys Lys Leu Glu Ser Ser Glu Glu Asn Leu Ser Ser 1205 1210 1215 Glu Asp Glu Glu Leu Pro Cys Phe Gln His Leu Leu Phe Gly Lys 1220 1225 1230 Val Asn Asn Ile Pro Ser Gln Ser Thr Arg His Ser Thr Val Ala 1235 1240 1245 Thr Glu Cys Leu Ser Lys Asn Thr Glu Glu Asn Leu Leu Ser Leu 1250 1255 1260 Lys Asn Ser Leu Asn Asp Cys Ser Asn Gln Val Ile Leu Ala Lys 1265 1270 1275 Ala Ser Gln Glu His His Leu Ser Glu Glu Thr Lys Cys Ser Ala 1280 1285 1290 Ser Leu Phe Ser Ser Gln Cys Ser Glu Leu Glu Asp Leu Thr Ala 1295 1300 1305 Asn Thr Asn Thr Gln Asp Pro Phe Leu Ile Gly Ser Ser Lys Gln 1310 1315 1320 Met Arg His Gln Ser Glu Ser Gln Gly Val Gly Leu Ser Asp Lys 1325 1330 1335 Glu Leu Val Ser Asp Asp Glu Glu Arg Gly Thr Gly Leu Glu Glu 1340 1345 1350 Asn Asn Gln Glu Glu Gln Ser Met Asp Ser Asn Leu Gly Glu Ala 1355 1360 1365 Ala Ser Gly Cys Glu Ser Glu Thr Ser Val Ser Glu Asp Cys Ser 1370 1375 1380 Gly Leu Ser Ser Gln Ser Asp Ile Leu Thr Thr Gln Gln Arg Asp 1385 1390 1395 Thr Met Gln His Asn Leu Ile Lys Leu Gln Gln Glu Met Ala Glu 1400 1405 1410 Leu Glu Ala Val Leu Glu Gln His Gly Ser Gln Pro Ser Asn Ser 1415 1420 1425 Tyr Pro Ser Ile Ile Ser Asp Ser Ser Ala Leu Glu Asp Leu Arg 1430 1435 1440 Asn Pro Glu Gln Ser Thr Ser Glu Lys Ala Val Leu Thr Ser Gln 1445 1450 1455 Lys Ser Ser Glu Tyr Pro Ile Ser Gln Asn Pro Glu Gly Leu Ser 1460 1465 1470 Ala Asp Lys Phe Glu Val Ser Ala Asp Ser Ser Thr Ser Lys Asn 1475 1480 1485 Lys Glu Pro Gly Val Glu Arg Ser Ser Pro Ser Lys Cys Pro Ser 1490 1495 1500 Leu Asp Asp Arg Trp Tyr Met His Ser Cys Ser Gly Ser Leu Gln 1505 1510 1515 Asn Arg Asn Tyr Pro Ser Gln Glu Glu Leu Ile Lys Val Val Asp 1520 1525 1530 Val Glu Glu Gln Gln Leu Glu Glu Ser Gly Pro His Asp Leu Thr 1535 1540 1545 Glu Thr Ser Tyr Leu Pro Arg Gln Asp Leu Glu Gly Thr Pro Tyr 1550 1555 1560 Leu Glu Ser Gly Ile Ser Leu Phe Ser Asp Asp Pro Glu Ser Asp 1565 1570 1575 Pro Ser Glu Asp Arg Ala Pro Glu Ser Ala Arg Val Gly Asn Ile 1580 1585 1590 Pro Ser Ser Thr Ser Ala Leu Lys Val Pro Gln Leu Lys Val Ala 1595 1600 1605 Glu Ser Ala Gln Ser Pro Ala Ala Ala His Thr Thr Asp Thr Ala 1610 1615 1620 Gly Tyr Asn Ala Met Glu Glu Ser Val Ser Arg Glu Lys Pro Glu 1625 1630 1635 Leu Thr Ala Ser Thr Glu Arg Val Asn Lys Arg Met Ser Met Val 1640 1645 1650 Val Ser Gly Leu Thr Pro Glu Glu Phe Met Leu Val Tyr Lys Phe 1655 1660 1665 Ala Arg Lys His His Ile Thr Leu Thr Asn Leu Ile Thr Glu Glu 1670 1675 1680 Thr Thr His Val Val Met Lys Thr Asp Ala Glu Phe Val Cys Glu 1685 1690 1695 Arg Thr Leu Lys Tyr Phe Leu Gly Ile Ala Gly Gly Lys Trp Val 1700 1705 1710 Val Ser Tyr Phe Trp Val Thr Gln Ser Ile Lys Glu Arg Lys Met 1715 1720 1725 Leu Asn Glu His Asp Phe Glu Val Arg Gly Asp Val Val Asn Gly 1730 1735 1740 Arg Asn His Gln Gly Pro Lys Arg Ala Arg Glu Ser Gln Asp Arg 1745 1750 1755 Lys Ile Phe Arg Gly Leu Glu Ile Cys Cys Tyr Gly Pro Phe Thr 1760 1765 1770 Asn Met Pro Thr Asp Gln Leu Glu Trp Met Val Gln Leu Cys Gly 1775 1780 1785 Ala Ser Val Val Lys Glu Leu Ser Ser Phe Thr Leu Gly Thr Gly 1790 1795 1800 Val His Pro Ile Val Val Val Gln Pro Asp Ala Trp Thr Glu Asp 1805 1810 1815 Asn Gly Phe His Ala Ile Gly Gln Met Cys Glu Ala Pro Val Val 1820 1825 1830 Thr Arg Glu Trp Val Leu Asp Ser Val Ala Leu Tyr Gln Cys Gln 1835 1840 1845 Glu Leu Asp Thr Tyr Leu Ile Pro Gln Ile Pro His Ser His Tyr 1850 1855 1860 3 339 PRT Homo sapiens 3 Met Ala Met Gln Met Gln Leu Glu Ala Asn Ala Asp Thr Ser Val Glu 1 5 10 15 Glu Glu Ser Phe Gly Pro Gln Pro Ile Ser Arg Leu Glu Gln Cys Gly 20 25 30 Ile Asn Ala Asn Asp Val Lys Lys Leu Glu Glu Ala Gly Phe His Thr 35 40 45 Val Glu Ala Val Ala Tyr Ala Pro Lys Lys Glu Leu Ile Asn Ile Lys 50 55 60 Gly Ile Ser Glu Ala Lys Ala Asp Lys Ile Leu Ala Glu Ala Ala Lys 65 70 75 80 Leu Val Pro Met Gly Phe Thr Thr Ala Thr Glu Phe His Gln Arg Arg 85 90 95 Ser Glu Ile Ile Gln Ile Thr Thr Gly Ser Lys Glu Leu Asp Lys Leu 100 105 110 Leu Gln Gly Gly Ile Glu Thr Gly Ser Ile Thr Glu Met Phe Gly Glu 115 120 125 Phe Arg Thr Gly Lys Thr Gln Ile Cys His Thr Leu Ala Val Thr Cys 130 135 140 Gln Leu Pro Ile Asp Arg Gly Gly Gly Glu Gly Lys Ala Met Tyr Ile 145 150 155 160 Asp Thr Glu Gly Thr Phe Arg Pro Glu Arg Leu Leu Ala Val Ala Glu 165 170 175 Arg Tyr Gly Leu Ser Gly Ser Asp Val Leu Asp Asn Val Ala Tyr Ala 180 185 190 Arg Ala Phe Asn Thr Asp His Gln Thr Gln Leu Leu Tyr Gln Ala Ser 195 200 205 Ala Met Met Val Glu Ser Arg Tyr Ala Leu Leu Ile Val Asp Ser Ala 210 215 220 Thr Ala Leu Tyr Arg Thr Asp Tyr Ser Gly Arg Gly Glu Leu Ser Ala 225 230 235 240 Arg Gln Met His Leu Ala Arg Phe Leu Arg Met Leu Leu Arg Leu Ala 245 250 255 Asp Glu Phe Gly Val Ala Val Val Ile Thr Asn Gln Val Val Ala Gln 260 265 270 Val Asp Gly Ala Ala Met Phe Ala Ala Asp Pro Lys Lys Pro Ile Gly 275 280 285 Gly Asn Ile Ile Ala His Ala Ser Thr Thr Arg Leu Tyr Leu Arg Lys 290 295 300 Gly Arg Gly Glu Thr Arg Ile Cys Lys Ile Tyr Asp Ser Pro Cys Leu 305 310 315 320 Pro Glu Ala Glu Ala Met Phe Ala Ile Asn Ala Asp Gly Val Gly Asp 325 330 335 Ala Lys Asp 4 2626 PRT Homo sapiens 4 Met Thr Thr Glu Leu Ser Ser Tyr Gly Tyr Leu Gly Ser Glu Asn Ser 1 5 10 15 Ala Leu Phe Asn Arg Val Cys Thr Ser Tyr Cys Glu Glu Gly Val Glu 20 25 30 Ser Ala Ala Leu Leu Gly Cys Asp Asn Ser Ser Ser Thr Gly Asn Thr 35 40 45 Ser Phe Ser Ser Leu Leu Arg Asp Tyr Pro Leu His Leu Phe His Met 50 55 60 Lys Thr Pro Phe Pro Leu Ser Phe Ile Glu Cys Pro Ser Lys Ser Glu 65 70 75 80 Leu Thr Ser Leu Gly Ile Ile Leu Tyr Phe Leu Asp Asp Met Glu Asp 85 90 95 Glu Ile Phe Arg His Tyr Ala Glu Leu Arg Pro Gln Asn Phe Pro Cys 100 105 110 Ser Val Arg Arg Asn Asn Ser Ala Phe Met Thr Ser Ser Asp Phe Ala 115 120 125 Glu Arg Ala Ala Gly Val Tyr His Arg Glu Ala Arg Ser Gly Lys Tyr 130 135 140 Lys Leu Thr Tyr Ala Glu Ala Lys Ala Val Cys Glu Phe Glu Gly Gly 145 150 155 160 His Leu Ala Thr Tyr Lys Gln Leu Glu Ala Ala Arg Lys Ile Gly Phe 165 170 175 His Val Cys Ala Ala Gly Trp Met Ala Lys Gly Arg Val Gly Tyr Pro 180 185 190 Ile Val Lys Pro Gly Pro Asn Cys Gly Phe Gly Lys Thr Gly Ile Ile 195 200 205 Asp Tyr Gly Ile Arg Leu Asn Arg Ser Glu Arg Trp Asp Ala Tyr Cys 210 215 220 Tyr Asn Pro His Ala Lys Glu Cys Gly Gly Val Phe Thr Asp Pro Lys 225 230 235 240 Gln Ile Phe Lys Ser Pro Gly Phe Pro Asn Glu Tyr Glu Asp Asn Gln 245 250 255 Ile Cys Tyr Trp His Ile Arg Leu Lys Tyr Gly Gln Arg Ile His Leu 260 265 270 Ser Phe Leu Asp Phe Asp Leu Glu Asp Asp Pro Gly Cys Leu Ala Asp 275 280 285 Tyr Val Glu Ile Tyr Asp Ser Tyr Asp Asp Val His Gly Phe Val Gly 290 295 300 Arg Tyr Cys Gly Asp Glu Leu Pro Asp Asp Ile Ile Ser Thr Gly Asn 305 310 315 320 Val Met Thr Leu Lys Phe Leu Ser Asp Ala Ser Val Thr Ala Gly Gly 325 330 335 Phe Gln Ile Lys Tyr Val Ala Met Asp Pro Val Ser Lys Ser Ser Gln 340 345 350 Gly Lys Asn Thr Lys Val Arg Met Gln Arg Asp Leu Val Asp Thr Ala 355 360 365 Gln Arg Ser Ala Pro Gly Pro Ser Ala Arg Arg Arg Val Ala Asp Met 370 375 380 Thr Ala Arg Gly Gln Ser Pro Leu Ala Pro Leu Leu Glu Thr Leu Glu 385 390 395 400 Asp Pro Ser Ala Ser His Gly Gly Gln Thr Asp Ala Tyr Leu Thr Leu 405 410 415 Thr Ser Arg Met Thr Gly Glu Glu Gly Lys Glu Val Ile Thr Glu Ile 420 425 430 Glu Lys Lys Leu Pro Arg Leu Tyr Lys Val Leu Lys Val Ser Ser Ile 435 440 445 Ile Asp Ser Leu Glu Ile Leu Phe Asn Lys Gly Glu Thr His Ser Ala 450 455 460 Val Val Asp Phe Glu Ala Leu Asn Val Ile Val Arg Leu Ile Glu Gln 465 470 475 480 Ala Pro Ile Gln Met Gly Glu Glu Ala Val Arg Trp Ala Lys Leu Val 485 490 495 Ile Pro Leu Val Val His Ser Ala Gln Lys Val His Leu Arg Gly Ala 500 505 510 Thr Ala Leu Glu Met Gly Met Pro Leu Leu Leu Gln Lys Gln Gln Glu 515 520 525 Ile Ala Ser Ile Thr Glu Gln Leu Met Thr Thr Thr Leu His Arg Ser 530 535 540 Gly Ser Phe Ile Asn Ser Leu Leu Gln Leu Glu Glu Leu Gly Phe Arg 545 550 555 560 Ser Gly Ala Pro Met Ile Lys Lys Ile Ala Phe Ile Ala Trp Lys Ser 565 570 575 Leu Ile Asp Asn Phe Ala Leu Asn Pro Asp Ile Leu Cys Ser Ala Lys 580 585 590 Arg Leu Lys Leu Leu Met Gln Pro Leu Ser Ser Ile His Val Arg Thr 595 600 605 Glu Thr Leu Ala Leu Thr Lys Leu Glu Val Trp Trp Tyr Leu Leu Met 610 615 620 Arg Leu Gly Pro His Leu Pro Ala Asn Phe Glu Gln Val Cys Val Pro 625 630 635 640 Leu Ile Gln Ser Thr Ile Ser Ile Asp Ser Asn Ala Ser Pro Gln Gly 645 650 655 Asn Ser Cys His Val Ala Thr Ser Pro Gly Leu Asn Pro Met Thr Pro 660 665 670 Val His Lys Gly Ala Ser Ser Pro Tyr Gly Ala Pro Gly Thr Pro Arg 675 680 685 Met Asn Leu Ser Ser Asn Leu Gly Gly Met Ala Thr Ile Pro Ser Ile 690 695 700 Gln Leu Leu Gly Leu Glu Met Leu Leu His Phe Leu Leu Gly Pro Glu 705 710 715 720 Ala Leu Ser Phe Ala Lys Gln Asn Lys Leu Val Leu Ser Leu Glu Pro 725 730 735 Leu Glu His Pro Leu Ile Ser Ser Pro Ser Phe Phe Ser Lys His Ala 740 745 750 Asn Thr Leu Ile Thr Ala Val His Asp Ser Phe Val Ala Val Gly Lys 755 760 765 Asp Ala Pro Gly Asn Lys Lys Glu Lys Pro Gly Ser Glu Val Leu Thr 770 775 780 Leu Leu Leu Lys Ser Leu Glu Ser Ile Val Lys Ser Glu Val Phe Pro 785 790 795 800 Val Ser Lys Thr Leu Gly Thr Pro Ala Leu Phe Leu Ile Gln Leu Ile 805 810 815 Phe Asn Asn Phe Leu Glu Cys Gly Val Ser Asp Glu Arg Phe Phe Leu 820 825 830 Ser Leu Glu Ser Leu Val Gly Cys Val Leu Ser Gly Pro Thr Ser Pro 835 840 845 Leu Ala Phe Ser Asp Ser Val Leu Asn Val Ile Asn Gln Asn Ala Lys 850 855 860 Gln Leu Glu Asn Lys Glu His Leu Trp Lys Met Trp Ser Val Ile Val 865 870 875 880 Thr Pro Leu Thr Glu Leu Ile Asn Gln Thr Asn Glu Val Asn Gln Gly 885 890 895 Asp Ala Leu Glu His Asn Phe Ser Ala Ile Tyr Gly Ala Leu Thr Leu 900 905 910 Pro Val Asn His Ile Phe Ser Glu Gln Arg Phe Pro Val Ala Thr Met 915 920 925 Lys Thr Leu Leu Arg Thr Trp Ser Glu Leu Tyr Arg Ala Phe Ala Arg 930 935 940 Cys Ala Ala Leu Val Ala Thr Ala Glu Glu Asn Leu Cys Cys Glu Glu 945 950 955 960 Leu Ser Ser Lys Ile Met Ser Ser Leu Glu Asp Glu Gly Phe Ser Asn 965 970 975 Leu Leu Phe Val Asp Arg Ile Ile Tyr Ile Ile Thr Val Met Val Asp 980 985 990 Cys Ile Asp Phe Ser Pro Tyr Asn Ile Lys Tyr Gln Pro Lys Val Lys 995 1000 1005 Ser Pro Gln Arg Pro Ser Asp Trp Ser Lys Lys Lys Asn Glu Pro 1010 1015 1020 Leu Gly Lys Leu Thr Ser Leu Phe Lys Leu Ile Val Lys Val Ile 1025 1030 1035 Tyr Ser Phe His Thr Leu Ser Phe Lys Glu Ala His Ser Asp Thr 1040 1045 1050 Leu Phe Thr Ile Gly Asn Ser Ile Thr Gly Ile Ile Ser Ser Val 1055 1060 1065 Leu Gly His Ile Ser Leu Pro Ser Met Ile Arg Lys Ile Phe Ala 1070 1075 1080 Thr Leu Thr Arg Pro Leu Ala Leu Phe Tyr Glu Asn Ser Lys Leu 1085 1090 1095 Asp Glu Val Pro Lys Val Tyr Ser Cys Leu Asn Asn Lys Leu Glu 1100 1105 1110 Lys Leu Leu Gly Glu Ile Ile Ala Cys Leu Gln Phe Ser Tyr Thr 1115 1120 1125 Gly Thr Tyr Asp Ser Glu Leu Leu Glu Gln Leu Ser Pro Leu Leu 1130 1135 1140 Cys Ile Ile Phe Leu His Lys Asn Lys Gln Ile Arg Lys Gln Ser 1145 1150 1155 Ala Gln Phe Trp Asn Ala Thr Phe Ala Lys Val Met Met Leu Val 1160 1165 1170 Tyr Pro Glu Glu Leu Lys Pro Val Leu Thr Gln Ala Lys Gln Lys 1175 1180 1185 Phe Leu Leu Leu Leu Pro Gly Leu Glu Thr Val Glu Met Met Glu 1190 1195 1200 Glu Ser Ser Gly Pro Tyr Ser Asp Gly Leu Lys Leu Glu Ser Ser 1205 1210 1215 Ser Leu Lys Val Lys Gly Glu Ile Leu Leu Glu Glu Glu Lys Ser 1220 1225 1230 Thr Asp Phe Val Phe Ile Pro Pro Glu Gly Lys Asp Ala Lys Glu 1235 1240 1245 Arg Ile Leu Thr Asp His Gln Lys Glu Val Leu Lys Thr Lys Arg 1250 1255 1260 Phe Glu Glu Gln Met Asp Ser Asp Ile Val Ile Pro Gln Asp Val 1265 1270 1275 Thr Glu Asp Cys Gly Met Ala Glu His Leu Glu Lys Ser Ser Leu 1280 1285 1290 Ser Asn Asn Glu Cys Gly Ser Leu Asp Lys Thr Ser Pro Glu Met 1295 1300 1305 Ser Asn Ser Asn Asn Asp Glu Arg Lys Lys Ala Leu Ile Ser Ser 1310 1315 1320 Arg Lys Thr Ser Thr Glu Cys Ala Ser Ser Thr Glu Asn Ser Phe 1325 1330 1335 Val Val Ser Ser Ser Ser Val Ser Asn Thr Thr Val Ala Gly Thr 1340 1345 1350 Pro Pro Tyr Pro Thr Ser Arg Arg Gln Thr Phe Ile Thr Leu Glu 1355 1360 1365 Lys Phe Asp Gly Ser Glu Asn Arg Pro Phe Ser Pro Ser Pro Leu 1370 1375 1380 Asn Asn Ile Ser Ser Thr Val Thr Val Lys Asn Asn Gln Glu Thr 1385 1390 1395 Met Ile Lys Thr Asp Phe Leu Pro Lys Ala Lys Gln Arg Glu Gly 1400 1405 1410 Thr Phe Ser Lys Ser Asp Ser Glu Lys Ile Val Asn Gly Thr Lys 1415 1420 1425 Arg Ser Ser Arg Arg Ala Gly Lys Ala Glu Gln Thr Gly Asn Lys 1430 1435 1440 Arg Ser Lys Pro Leu Met Arg Ser Glu Pro Glu Lys Asn Thr Glu 1445 1450 1455 Glu Ser Val Glu Gly Ile Val Val Leu Glu Asn Asn Pro Pro Gly 1460 1465 1470 Leu Leu Asn Gln Thr Glu Cys Val Ser Asp Asn Gln Val His Leu 1475 1480 1485 Ser Glu Ser Thr Met Glu His Asp Asn Thr Lys Leu Lys Ala Ala 1490 1495 1500 Thr Val Glu Asn Ala Val Leu Leu Glu Thr Asn Thr Val Glu Glu 1505 1510 1515 Lys Asn Val Glu Ile Asn Leu Glu Ser Lys Glu Asn Thr Pro Pro 1520 1525 1530 Val Val Ile Ser Ala Asp Gln Met Val Asn Glu Asp Ser Gln Val 1535 1540 1545 Gln Ile Thr Pro Asn Gln Lys Thr Leu Arg Arg Ser Ser Arg Arg 1550 1555 1560 Arg Ser Glu Val Val Glu Ser Thr Thr Glu Ser Gln Asp Lys Glu 1565 1570 1575 Asn Ser His Gln Lys Lys Glu Arg Arg Lys Glu Glu Glu Lys Pro 1580 1585 1590 Leu Gln Lys Ser Pro Leu His Ile Lys Asp Asp Val Leu Pro Lys 1595 1600 1605 Gln Lys Leu Ile Ala Glu Gln Thr Leu Gln Glu Asn Leu Ile Glu 1610 1615 1620 Lys Gly Ser Asn Leu His Glu Lys Thr Leu Gly Glu Thr Ser Ala 1625 1630 1635 Asn Ala Glu Thr Glu Gln Asn Lys Lys Lys Ala Asp Pro Glu Asn 1640 1645 1650 Ile Lys Ser Glu Gly Asp Gly Thr Gln Asp Ile Val Asp Lys Ser 1655 1660 1665 Ser Glu Lys Leu Val Arg Gly Arg Thr Arg Tyr Gln Thr Arg Arg 1670 1675 1680 Ala Ser Gln Gly Leu Leu Ser Ser Ile Glu Asn Ser Glu Ser Asp 1685 1690 1695 Ser Ser Glu Ala Lys Glu Glu Gly Ser Arg Lys Lys Arg Ser Gly 1700 1705 1710 Lys Trp Lys Asn Lys Ser Asn Glu Ser Val Asp Ile Gln Asp Gln 1715 1720 1725 Glu Glu Lys Val Val Lys Gln Glu Cys Ile Lys Ala Glu Asn Gln 1730 1735 1740 Ser His Asp Tyr Lys Ala Thr Ser Glu Glu Asp Val Ser Ile Lys 1745 1750 1755 Ser Pro Ile Cys Glu Lys Gln Asp Glu Ser Asn Thr Val Ile Cys 1760 1765 1770 Gln Asp Ser Thr Val Thr Ser Asp Leu Leu Gln Val Pro Asp Asp 1775 1780 1785 Leu Pro Asn Val Cys Glu Glu Lys Asn Glu Thr Ser Lys Tyr Ala 1790 1795 1800 Glu Tyr Ser Phe Thr Ser Leu Pro Val Pro Glu Ser Asn Leu Arg 1805 1810 1815 Thr Arg Asn Ala Ile Lys Arg Leu His Lys Arg Asp Ser Phe Asp 1820 1825 1830 Asn Cys Ser Leu Gly Glu Ser Ser Lys Ile Gly Ile Ser Asp Ile 1835 1840 1845 Ser Ser Leu Ser Glu Lys Thr Phe Gln Thr Leu Glu Cys Gln His 1850 1855 1860 Lys Arg Ser Arg Arg Val Arg Arg Ser Lys Gly Cys Asp Cys Cys 1865 1870 1875 Gly Glu Lys Ser Gln Pro Gln Glu Lys Ser Leu Ile Gly Leu Lys 1880 1885 1890 Asn Thr Glu Asn Asn Asp Val Glu Ile Ser Glu Thr Lys Lys Ala 1895 1900 1905 Asp Val Gln Ala Pro Val Ser Pro Ser Glu Thr Ser Gln Ala Asn 1910 1915 1920 Pro Tyr Ser Glu Gly Gln Phe Leu Asp Glu His His Ser Val Asn 1925 1930 1935 Phe His Leu Gly Leu Lys Glu Asp Asn Asp Thr Ile Asn Asp Ser 1940 1945 1950 Leu Ile Val Ser Glu Thr Lys Ser Lys Glu Asn Thr Met Gln Glu 1955 1960 1965 Ser Leu Pro Ser Gly Ile Val Asn Phe Arg Glu Glu Ile Cys Asp 1970 1975 1980 Met Asp Ser Ser Glu Ala Met Ser Leu Glu Ser Gln Glu Ser Pro 1985 1990 1995 Asn Glu Asn Phe Lys Thr Val Gly Pro Cys Leu Gly Asp Ser Lys 2000 2005 2010 Asn Val Ser Gln Glu Ser Leu Glu Thr Lys Glu Glu Lys Pro Glu 2015 2020 2025 Glu Thr Pro Lys Met Glu Leu Ser Leu Glu Asn Val Thr Val Glu 2030 2035 2040 Gly Asn Ala Cys Lys Val Thr Glu Ser Asn Leu Glu Lys Ala Lys 2045 2050 2055 Thr Met Glu Leu Asn Val Gly Asn Glu Ala Ser Phe His Gly Gln 2060 2065 2070 Glu Arg Thr Lys Thr Gly Ile Ser Glu Glu Ala Ala Ile Glu Glu 2075 2080 2085 Asn Lys Arg Asn Asp Asp Ser Glu Ala Asp Thr Ala Lys Leu Asn 2090 2095 2100 Ala Lys Glu Val Ala Thr Glu Glu Phe Asn Ser Asp Ile Ser Leu 2105 2110 2115 Ser Asp Asn Thr Thr Pro Val Lys Leu Asn Ala Gln Thr Glu Ile 2120 2125 2130 Ser Glu Gln Thr Ala Ala Gly Glu Leu Asp Gly Gly Asn Asp Val 2135 2140 2145 Ser Asp Leu His Ser Ser Glu Glu Thr Asn Thr Lys Met Lys Asn 2150 2155 2160 Asn Glu Glu Met Met Ile Gly Glu Ala Met Ala Glu Thr Gly His 2165 2170 2175 Asp Gly Glu Thr Glu Asn Glu Gly Ile Thr Thr Lys Thr Ser Lys 2180 2185 2190 Pro Asp Glu Ala Glu Thr Asn Met Leu Thr Ala Glu Met Asp Asn 2195 2200 2205 Phe Val Cys Asp Thr Val Glu Met Ser Thr Glu Glu Gly Ile Ile 2210 2215 2220 Asp Ala Asn Lys Thr Glu Thr Asn Thr Glu Tyr Ser Lys Ser Glu 2225 2230 2235 Glu Lys Leu Asp Asn Asn Gln Met Val Met Glu Ser Asp Ile Leu 2240 2245 2250 Gln Glu Asp His His Thr Ser Gln Lys Val Glu Glu Pro Ser Gln 2255 2260 2265 Cys Leu Ala Ser Gly Thr Ala Ile Ser Glu Leu Ile Ile Glu Asp 2270 2275 2280 Asn Asn Ala Ser Pro Gln Lys Leu Arg Glu Leu Asp Pro Ser Leu 2285 2290 2295 Val Ser Ala Asn Asp Ser Pro Ser Gly Met Gln Thr Arg Cys Val 2300 2305 2310 Trp Ser Pro Leu Ala Ser Pro Ser Thr Ser Ile Leu Lys Arg Gly 2315 2320 2325 Leu Lys Arg Ser Gln Glu Asp Glu Ile Ser Ser Pro Val Asn Lys 2330 2335 2340 Val Arg Arg Val Ser Phe Ala Asp Pro Ile Tyr Gln Ala Gly Leu 2345 2350 2355 Ala Asp Asp Ile Asp Arg Arg Cys Ser Ile Val Arg Ser His Ser 2360 2365 2370 Ser Asn Ser Ser Pro Ile Gly Lys Ser Val Lys Thr Ser Pro Thr 2375 2380 2385 Thr Gln Ser Lys Ser Val Asp Leu Cys Val Thr Ala Ser Glu Ile 2390 2395 2400 Tyr Ser Lys Ile Ser Glu Met Ala Lys Glu Ser Ile Pro Cys Pro 2405 2410 2415 Thr Glu Ser Val Tyr Pro Pro Leu Val Asn Cys Val Ala Pro Val 2420 2425 2430 Asp Ile Ile Leu Pro Gln Ile Thr Ser Asn Met Trp Ala Arg Gly 2435 2440 2445 Leu Gly Gln Leu Ile Arg Ala Lys Asn Ile Lys Thr Ile Gly Asp 2450 2455 2460 Leu Ser Thr Leu Thr Ala Ser Glu Ile Lys Thr Leu Pro Ile Arg 2465 2470 2475 Ser Pro Lys Val Ser Asn Val Lys Lys Ala Leu Arg Ile Tyr His 2480 2485 2490 Glu Gln Gln Val Lys Thr Arg Gly Leu Glu Glu Ile Pro Val Phe 2495 2500 2505 Asp Ile Ser Glu Lys Thr Val Asn Gly Ile Glu Asn Lys Ser Leu 2510 2515 2520 Ser Pro Asp Glu Glu Arg Leu Val Ser Asp Ile Ile Asp Pro Val 2525 2530 2535 Ala Leu Glu Ile Pro Leu Ser Lys Asn Leu Leu Ala Gln Ile Ser 2540 2545 2550 Ala Leu Ala Leu Gln Leu Asp Ser Glu Asp Leu His Asn Tyr Ser 2555 2560 2565 Gly Ser Gln Leu Phe Glu Met His Glu Lys Leu Ser Ser Glu Gly 2570 2575 2580 Ile Phe Leu Ala Thr Val Cys Gln Phe Ile Ile Val Asp Lys Ala 2585 2590 2595 Glu Phe Thr Gly Gln Gln Ala Tyr Met Leu Ile Glu Val Asp Ala 2600 2605 2610 Leu Arg Ser Asp Glu Leu Lys Arg Met Glu Lys Ala Asp 2615 2620 2625 5 1186 PRT Homo sapiens 5 Met Asp Glu Pro Pro Gly Lys Pro Leu Ser Cys Glu Glu Lys Glu Lys 1 5 10 15 Leu Lys Glu Lys Leu Ala Phe Leu Lys Arg Glu Tyr Ser Lys Thr Leu 20 25 30 Ala Arg Leu Gln Arg Ala Gln Arg Ala Glu Lys Ile Lys His Ser Ile 35 40 45 Lys Lys Thr Val Glu Glu Gln Asp Cys Leu Ser Gln Gln Asp Leu Ser 50 55 60 Pro Gln Leu Lys His Ser Glu Pro Lys Asn Lys Ile Cys Val Tyr Asp 65 70 75 80 Lys Leu His Ile Lys Thr His Leu Asp Glu Glu Thr Gly Glu Lys Thr 85 90 95 Ser Ile Thr Leu Asp Val Gly Pro Glu Ser Phe Asn Pro Gly Asp Gly 100 105 110 Pro Gly Gly Leu Pro Ile Gln Arg Thr Asp Asp Thr Gln Glu His Phe 115 120 125 Pro His Arg Val Ser Asp Pro Ser Gly Glu Gln Lys Gln Lys Leu Pro 130 135 140 Ser Arg Arg Lys Lys Gln Gln Lys Arg Thr Phe Ile Ser Gln Glu Arg 145 150 155 160 Asp Cys Val Phe Gly Thr Asp Ser Leu Arg Leu Ser Gly Lys Arg Leu 165 170 175 Lys Glu Gln Glu Glu Ile Ser Ser Lys Asn Pro Ala Arg Ser Pro Val 180 185 190 Thr Glu Ile Arg Thr His Leu Leu Ser Leu Lys Ser Glu Leu Pro Asp 195 200 205 Ser Pro Glu Pro Val Thr Glu Ile Asn Glu Asp Ser Val Leu Ile Pro 210 215 220 Pro Thr Ala Gln Pro Glu Lys Gly Val Asp Thr Phe Leu Arg Arg Pro 225 230 235 240 Asn Phe Thr Arg Ala Thr Thr Val Pro Leu Gln Thr Leu Ser Asp Ser 245 250 255 Gly Ser Ser Gln His Leu Glu His Ile Pro Pro Lys Gly Ser Ser Glu 260 265 270 Leu Thr Thr His Asp Leu Lys Asn Ile Arg Phe Thr Ser Pro Val Ser 275 280 285 Leu Glu Ala Gln Gly Lys Lys Met Thr Val Ser Thr Asp Asn Leu Leu 290 295 300 Val Asn Lys Ala Ile Ser Lys Ser Gly Gln Leu Pro Thr Ser Ser Asn 305 310 315 320 Leu Glu Ala Asn Ile Ser Cys Ser Leu Asn Glu Leu Thr Tyr Asn Asn 325 330 335 Leu Pro Ala Asn Glu Asn Gln Asn Leu Lys Glu Gln Asn Gln Thr Glu 340 345 350 Lys Ser Leu Lys Ser Pro Ser Asp Thr Leu Asp Gly Arg Asn Glu Asn 355 360 365 Leu Gln Glu Ser Glu Ile Leu Ser Gln Pro Lys Ser Leu Ser Leu Glu 370 375 380 Ala Thr Ser Pro Leu Ser Ala Glu Lys His Ser Cys Thr Val Pro Glu 385 390 395 400 Gly Leu Leu Phe Pro Ala Glu Tyr Tyr Val Arg Thr Thr Arg Ser Met 405 410 415 Ser Asn Cys Gln Arg Lys Val Ala Val Glu Ala Val Ile Gln Ser His 420 425 430 Leu Asp Val Lys Lys Lys Gly Phe Lys Asn Lys Asn Lys Asp Ala Ser 435 440 445 Lys Asn Leu Asn Leu Ser Asn Glu Glu Thr Asp Gln Ser Glu Ile Arg 450 455 460 Met Ser Gly Thr Cys Thr Gly Gln Pro Ser Ser Arg Thr Ser Gln Lys 465 470 475 480 Leu Leu Ser Leu Thr Lys Val Ser Ser Pro Ala Gly Pro Thr Glu Asp 485 490 495 Asn Asp Leu Ser Arg Lys Ala Val Ala Gln Ala Pro Gly Arg Arg Tyr 500 505 510 Thr Gly Lys Arg Lys Ser Ala Cys Thr Pro Ala Ser Asp His Cys Glu 515 520 525 Pro Leu Leu Pro Thr Ser Ser Leu Ser Ile Val Asn Arg Ser Lys Glu 530 535 540 Glu Val Thr Ser His Lys Tyr Gln His Glu Lys Leu Phe Ile Gln Val 545 550 555 560 Lys Gly Lys Lys Ser Arg His Gln Lys Glu Asp Ser Leu Ser Trp Ser 565 570 575 Asn Ser Ala Tyr Leu Ser Leu Asp Asp Asp Ala Phe Thr Ala Pro Phe 580 585 590 His Arg Asp Gly Met Leu Ser Leu Lys Gln Leu Leu Ser Phe Leu Ser 595 600 605 Ile Thr Asp Phe Gln Leu Pro Asp Glu Asp Phe Gly Pro Leu Lys Leu 610 615 620 Glu Lys Val Lys Ser Cys Ser Glu Lys Pro Val Glu Pro Phe Glu Ser 625 630 635 640 Lys Met Phe Gly Glu Arg His Leu Lys Glu Gly Ser Cys Ile Phe Pro 645 650 655 Glu Glu Leu Ser Pro Lys Arg Met Asp Thr Glu Met Glu Asp Leu Glu 660 665 670 Glu Asp Leu Ile Val Leu Pro Gly Lys Ser His Pro Lys Arg Pro Asn 675 680 685 Ser Gln Ser Gln His Thr Lys Thr Gly Leu Ser Ser Ser Ile Leu Leu 690 695 700 Tyr Thr Pro Leu Asn Thr Val Ala Pro Asp Asp Asn Asp Arg Pro Thr 705 710 715 720 Thr Asp Met Cys Ser Pro Ala Phe Pro Ile Leu Gly Thr Thr Pro Ala 725 730 735 Phe Gly Pro Gln Gly Ser Tyr Glu Lys Ala Ser Thr Glu Val Ala Gly 740 745 750 Arg Thr Cys Cys Thr Pro Gln Leu Ala His Leu Lys Asp Ser Val Cys 755 760 765 Leu Ala Ser Asp Thr Lys Gln Phe Asp Ser Ser Gly Ser Pro Ala Lys 770 775 780 Pro His Thr Thr Leu Gln Val Ser Gly Arg Gln Gly Gln Pro Thr Cys 785 790 795 800 Asp Cys Asp Ser Val Pro Pro Gly Thr Pro Pro Pro Ile Glu Ser Phe 805 810 815 Thr Phe Lys Glu Asn Gln Leu Cys Arg Asn Thr Cys Gln Glu Leu His 820 825 830 Lys His Ser Val Glu Gln Thr Glu Thr Ala Glu Leu Pro Ala Ser Asp 835 840 845 Ser Ile Asn Pro Gly Asn Leu Gln Leu Val Ser Glu Leu Lys Asn Pro 850 855 860 Ser Gly Ser Cys Ser Val Asp Val Ser Ala Met Phe Trp Glu Arg Ala 865 870 875 880 Gly Cys Lys Glu Pro Cys Ile Ile Thr Ala Cys Glu Asp Val Val Ser 885 890 895 Leu Trp Lys Ala Leu Asp Ala Trp Gln Trp Glu Lys Leu Tyr Thr Trp 900 905 910 His Phe Ala Glu Val Pro Val Leu Gln Ile Val Pro Val Pro Asp Val 915 920 925 Tyr Asn Leu Val Cys Val Ala Leu Gly Asn Leu Glu Ile Arg Glu Ile 930 935 940 Arg Ala Leu Phe Cys Ser Ser Asp Asp Glu Ser Glu Lys Gln Val Leu 945 950 955 960 Leu Lys Ser Gly Asn Ile Lys Ala Val Leu Gly Leu Thr Lys Arg Arg 965 970 975 Leu Val Ser Ser Ser Gly Thr Leu Ser Asp Gln Gln Val Glu Val Met 980 985 990 Thr Phe Ala Glu Asp Gly Gly Gly Lys Glu Asn Gln Phe Leu Met Pro 995 1000 1005 Pro Glu Glu Thr Ile Leu Thr Phe Ala Glu Val Gln Gly Met Gln 1010 1015 1020 Glu Ala Leu Leu Gly Thr Thr Ile Met Asn Asn Ile Val Ile Trp 1025 1030 1035 Asn Leu Lys Thr Gly Gln Leu Leu Lys Lys Met His Ile Asp Asp 1040 1045 1050 Ser Tyr Gln Ala Ser Val Cys His Lys Ala Tyr Ser Glu Met Gly 1055 1060 1065 Leu Leu Phe Ile Val Leu Ser His Pro Cys Ala Lys Glu Ser Glu 1070 1075 1080 Ser Leu Arg Ser Pro Val Phe Gln Leu Ile Val Ile Asn Pro Lys 1085 1090 1095 Thr Thr Leu Ser Val Gly Val Met Leu Tyr Cys Leu Pro Pro Gly 1100 1105 1110 Gln Ala Gly Arg Phe Leu Glu Gly Asp Val Lys Asp His Cys Ala 1115 1120 1125 Ala Ala Ile Leu Thr Ser Gly Thr Ile Ala Ile Trp Asp Leu Leu 1130 1135 1140 Leu Gly Gln Cys Thr Ala Leu Leu Pro Pro Val Ser Asp Gln His 1145 1150 1155 Trp Ser Phe Val Lys Trp Ser Gly Thr Asp Ser His Leu Leu Ala 1160 1165 1170 Gly Gln Lys Asp Gly Asn Ile Phe Val Tyr His Tyr Ser 1175 1180 1185 6 982 PRT Homo sapiens 6 Met Ala Pro Arg Leu Gln Leu Glu Lys Ala Ala Trp Arg Trp Ala Glu 1 5 10 15 Thr Val Arg Pro Glu Glu Val Ser Gln Glu His Ile Glu Thr Ala Tyr 20 25 30 Arg Ile Trp Leu Glu Pro Cys Ile Arg Gly Val Cys Arg Arg Asn Cys 35 40 45 Lys Gly Asn Pro Asn Cys Leu Val Gly Ile Gly Glu His Ile Trp Leu 50 55 60 Gly Glu Ile Asp Glu Asn Ser Phe His Asn Ile Asp Asp Pro Asn Cys 65 70 75 80 Glu Arg Arg Lys Lys Asn Ser Phe Val Gly Leu Thr Asn Leu Gly Ala 85 90 95 Thr Cys Tyr Val Asn Thr Phe Leu Gln Val Trp Phe Leu Asn Leu Glu 100 105 110 Leu Arg Gln Ala Leu Tyr Leu Cys Pro Ser Thr Cys Ser Asp Tyr Met 115 120 125 Leu Gly Asp Gly Ile Gln Glu Glu Lys Asp Tyr Glu Pro Gln Thr Ile 130 135 140 Cys Glu His Leu Gln Tyr Leu Phe Ala Leu Leu Gln Asn Ser Asn Arg 145 150 155 160 Arg Tyr Ile Asp Pro Ser Gly Phe Val Lys Ala Leu Gly Leu Asp Thr 165 170 175 Gly Gln Gln Gln Asp Ala Gln Glu Phe Ser Lys Leu Phe Met Ser Leu 180 185 190 Leu Glu Asp Thr Leu Ser Lys Gln Lys Asn Pro Asp Val Arg Asn Ile 195 200 205 Val Gln Gln Gln Phe Cys Gly Glu Tyr Ala Tyr Val Thr Val Cys Asn 210 215 220 Gln Cys Gly Arg Glu Ser Lys Leu Leu Ser Lys Phe Tyr Glu Leu Glu 225 230 235 240 Leu Asn Ile Gln Gly His Lys Gln Leu Thr Asp Cys Ile Ser Glu Phe 245 250 255 Leu Lys Glu Glu Lys Leu Glu Gly Asp Asn Arg Tyr Phe Cys Glu Asn 260 265 270 Cys Gln Ser Lys Gln Asn Ala Thr Arg Lys Ile Arg Leu Leu Ser Leu 275 280 285 Pro Cys Thr Leu Asn Leu Gln Leu Met Arg Phe Val Phe Asp Arg Gln 290 295 300 Thr Gly His Lys Lys Lys Leu Asn Thr Tyr Ile Gly Phe Ser Glu Ile 305 310 315 320 Leu Asp Met Glu Pro Tyr Val Glu His Lys Gly Gly Ser Tyr Val Tyr 325 330 335 Glu Leu Ser Ala Val Leu Ile His Arg Gly Val Ser Ala Tyr Ser Gly 340 345 350 His Tyr Ile Ala His Val Lys Asp Pro Gln Ser Gly Glu Trp Tyr Lys 355 360 365 Phe Asn Asp Glu Asp Ile Glu Lys Met Glu Gly Lys Lys Leu Gln Leu 370 375 380 Gly Ile Glu Glu Asp Leu Ala Glu Pro Ser Lys Ser Gln Thr Arg Lys 385 390 395 400 Pro Lys Cys Gly Lys Gly Thr His Cys Ser Arg Asn Ala Tyr Met Leu 405 410 415 Val Tyr Arg Leu Gln Thr Gln Glu Lys Pro Asn Thr Thr Val Gln Val 420 425 430 Pro Ala Phe Leu Gln Glu Leu Val Asp Arg Asp Asn Ser Lys Phe Glu 435 440 445 Glu Trp Cys Ile Glu Met Ala Glu Met Arg Lys Gln Ser Val Asp Lys 450 455 460 Gly Lys Ala Lys His Glu Glu Val Lys Glu Leu Tyr Gln Arg Leu Pro 465 470 475 480 Ala Gly Ala Glu Pro Tyr Glu Phe Val Ser Leu Glu Trp Leu Gln Lys 485 490 495 Trp Leu Asp Glu Ser Thr Pro Thr Lys Pro Ile Asp Asn His Ala Cys 500 505 510 Leu Cys Ser His Asp Lys Leu His Pro Asp Lys Ile Ser Ile Met Lys 515 520 525 Arg Ile Ser Glu Tyr Ala Ala Asp Ile Phe Tyr Ser Arg Tyr Gly Gly 530 535 540 Gly Pro Arg Leu Thr Val Lys Ala Leu Cys Lys Glu Cys Val Val Glu 545 550 555 560 Arg Cys Arg Ile Leu Arg Leu Lys Asn Gln Leu Asn Glu Asp Tyr Lys 565 570 575 Thr Val Asn Asn Leu Leu Lys Ala Ala Val Lys Gly Asp Gly Phe Trp 580 585 590 Val Gly Lys Ser Ser Leu Arg Ser Trp Arg Gln Leu Ala Leu Glu Gln 595 600 605 Leu Asp Glu Gln Asp Gly Asp Ala Glu Gln Ser Asn Gly Lys Met Asn 610 615 620 Gly Ser Thr Leu Asn Lys Asp Glu Ser Lys Glu Glu Arg Lys Glu Glu 625 630 635 640 Glu Glu Leu Asn Phe Asn Glu Asp Ile Leu Cys Pro His Gly Glu Leu 645 650 655 Cys Ile Ser Glu Asn Glu Arg Arg Leu Val Ser Lys Glu Ala Trp Ser 660 665 670 Lys Leu Gln Gln Tyr Phe Pro Lys Ala Pro Glu Phe Pro Ser Tyr Lys 675 680 685 Glu Cys Cys Ser Gln Cys Lys Ile Leu Glu Arg Glu Gly Glu Glu Asn 690 695 700 Glu Ala Leu His Lys Met Ile Ala Asn Glu Gln Lys Thr Ser Leu Pro 705 710 715 720 Asn Leu Phe Gln Asp Lys Asn Arg Pro Cys Leu Ser Asn Trp Pro Glu 725 730 735 Asp Thr Asp Val Leu Tyr Ile Val Ser Gln Phe Phe Val Glu Glu Trp 740 745 750 Arg Lys Phe Val Arg Lys Pro Thr Arg Cys Ser Pro Val Ser Ser Val 755 760 765 Gly Asn Ser Ala Leu Leu Cys Pro His Gly Gly Leu Met Phe Thr Phe 770 775 780 Ala Ser Met Thr Lys Glu Asp Ser Lys Leu Ile Ala Leu Ile Trp Pro 785 790 795 800 Ser Glu Trp Gln Met Ile Gln Lys Leu Phe Val Val Asp His Val Ile 805 810 815 Lys Ile Thr Arg Ile Glu Val Gly Asp Val Asn Pro Ser Glu Thr Gln 820 825 830 Tyr Ile Ser Glu Pro Lys Leu Cys Pro Glu Cys Arg Glu Gly Leu Leu 835 840 845 Cys Gln Gln Gln Arg Asp Leu Arg Glu Tyr Thr Gln Ala Thr Ile Tyr 850 855 860 Val His Lys Val Val Asp Asn Lys Lys Val Met Lys Asp Ser Ala Pro 865 870 875 880 Glu Leu Asn Val Ser Ser Ser Glu Thr Glu Glu Asp Lys Glu Glu Ala 885 890 895 Lys Pro Asp Gly Glu Lys Asp Pro Asp Phe Asn Gln Ile Met His Ala 900 905 910 Phe Ser Val Ala Pro Phe Asp Gln Asn Leu Ser Ile Asp Gly Lys Ile 915 920 925 Leu Ser Asp Asp Cys Ala Thr Leu Gly Thr Leu Gly Val Ile Pro Glu 930 935 940 Ser Val Ile Leu Leu Lys Ala Asp Glu Pro Ile Ala Asp Tyr Ala Ala 945 950 955 960 Met Asp Asp Val Met Gln Val Cys Met Pro Glu Glu Gly Phe Lys Gly 965 970 975 Thr Gly Leu Leu Gly His 980 7 721 PRT Homo sapiens 7 Met Asp Leu Ser Ala Leu Arg Val Glu Glu Val Gln Asn Val Ile Asn 1 5 10 15 Ala Met Gln Lys Ile Leu Glu Cys Pro Ile Cys Leu Glu Leu Ile Lys 20 25 30 Glu Pro Val Ser Thr Lys Cys Asp His Ile Phe Cys Lys Phe Cys Met 35 40 45 Leu Lys Leu Leu Asn Gln Lys Lys Gly Pro Ser Gln Cys Pro Leu Cys 50 55 60 Lys Asn Asp Ile Thr Lys Arg Ser Leu Gln Glu Ser Thr Arg Phe Ser 65 70 75 80 Gln Leu Val Glu Glu Leu Leu Lys Ile Ile Cys Ala Phe Gln Leu Asp 85 90 95 Thr Gly Leu Glu Tyr Ala Asn Ser Tyr Asn Phe Ala Lys Lys Glu Asn 100 105 110 Asn Ser Pro Glu His Leu Lys Asp Glu Val Ser Ile Ile Gln Ser Met 115 120 125 Gly Tyr Arg Asn Arg Ala Lys Arg Leu Leu Gln Ser Glu Pro Glu Asn 130 135 140 Pro Ser Leu Gln Glu Thr Ser Leu Ser Val Gln Leu Ser Asn Leu Gly 145 150 155 160 Thr Val Arg Thr Leu Arg Thr Lys Gln Arg Ile Gln Pro Gln Lys Thr 165 170 175 Ser Val Tyr Ile Glu Leu Gly Ser Asp Ser Ser Glu Asp Thr Val Asn 180 185 190 Lys Ala Thr Tyr Cys Ser Val Gly Asp Gln Glu Leu Leu Gln Ile Thr 195 200 205 Pro Gln Gly Thr Arg Asp Glu Ile Ser Leu Asp Ser Ala Lys Lys Gly 210 215 220 Glu Ala Ala Ser Gly Cys Glu Ser Glu Thr Ser Val Ser Glu Asp Cys 225 230 235 240 Ser Gly Leu Ser Ser Gln Ser Asp Ile Leu Thr Thr Gln Gln Arg Asp 245 250 255 Thr Met Gln His Asn Leu Ile Lys Leu Gln Gln Glu Met Ala Glu Leu 260 265 270 Glu Ala Val Leu Glu Gln His Gly Ser Gln Pro Ser Asn Ser Tyr Pro 275 280 285 Ser Ile Ile Ser Asp Ser Ser Ala Leu Glu Asp Leu Arg Asn Pro Glu 290 295 300 Gln Ser Thr Ser Glu Lys Ala Val Leu Thr Ser Gln Lys Ser Ser Glu 305 310 315 320 Tyr Pro Ile Ser Gln Asn Pro Glu Gly Leu Ser Ala Asp Lys Phe Glu 325 330 335 Val Ser Ala Asp Ser Ser Thr Ser Lys Asn Lys Glu Pro Gly Val Glu 340 345 350 Arg Ser Ser Pro Ser Lys Cys Pro Ser Leu Asp Asp Arg Trp Tyr Met 355 360 365 His Ser Cys Ser Gly Ser Leu Gln Asn Arg Asn Tyr Pro Ser Gln Glu 370 375 380 Glu Leu Ile Lys Val Val Asp Val Glu Glu Gln Gln Leu Glu Glu Ser 385 390 395 400 Gly Pro His Asp Leu Thr Glu Thr Ser Tyr Leu Pro Arg Gln Asp Leu 405 410 415 Glu Gly Thr Pro Tyr Leu Glu Ser Gly Ile Ser Leu Phe Ser Asp Asp 420 425 430 Pro Glu Ser Asp Pro Ser Glu Asp Arg Ala Pro Glu Ser Ala Arg Val 435 440 445 Gly Asn Ile Pro Ser Ser Thr Ser Ala Leu Lys Val Pro Gln Leu Lys 450 455 460 Val Ala Glu Ser Ala Gln Ser Pro Ala Ala Ala His Thr Thr Asp Thr 465 470 475 480 Ala Gly Tyr Asn Ala Met Glu Glu Ser Val Ser Arg Glu Lys Pro Glu 485 490 495 Leu Thr Ala Ser Thr Glu Arg Val Asn Lys Arg Met Ser Met Val Val 500 505 510 Ser Gly Leu Thr Pro Glu Glu Phe Met Leu Val Tyr Lys Phe Ala Arg 515 520 525 Lys His His Ile Thr Leu Thr Asn Leu Ile Thr Glu Glu Thr Thr His 530 535 540 Val Val Met Lys Thr Asp Ala Glu Phe Val Cys Glu Arg Thr Leu Lys 545 550 555 560 Tyr Phe Leu Gly Ile Ala Gly Gly Lys Trp Val Val Ser Tyr Phe Trp 565 570 575 Val Thr Gln Ser Ile Lys Glu Arg Lys Met Leu Asn Glu His Asp Phe 580 585 590 Glu Val Arg Gly Asp Val Val Asn Gly Arg Asn His Gln Gly Pro Lys 595 600 605 Arg Ala Arg Glu Ser Gln Asp Arg Lys Ile Phe Arg Gly Leu Glu Ile 610 615 620 Cys Cys Tyr Gly Pro Phe Thr Asn Met Pro Thr Asp Gln Leu Glu Trp 625 630 635 640 Met Val Gln Leu Cys Gly Ala Ser Val Val Lys Glu Leu Ser Ser Phe 645 650 655 Thr Leu Gly Thr Gly Val His Pro Ile Val Val Val Gln Pro Asp Ala 660 665 670 Trp Thr Glu Asp Asn Gly Phe His Ala Ile Gly Gln Met Cys Glu Ala 675 680 685 Pro Val Val Thr Arg Glu Trp Val Leu Asp Ser Val Ala Leu Tyr Gln 690 695 700 Cys Gln Glu Leu Asp Thr Tyr Leu Ile Pro Gln Ile Pro His Ser His 705 710 715 720 Tyr 8 719 PRT Homo sapiens 8 Met Pro Arg Arg Lys Lys Lys Val Lys Glu Val Ser Glu Ser Arg Asn 1 5 10 15 Leu Glu Lys Lys Asp Val Glu Thr Thr Ser Ser Val Ser Val Lys Arg 20 25 30 Lys Arg Arg Leu Glu Asp Ala Phe Ile Val Ile Ser Asp Ser Asp Gly 35 40 45 Glu Glu Pro Lys Glu Glu Asn Gly Leu Gln Lys Thr Lys Thr Lys Gln 50 55 60 Ser Asn Arg Ala Lys Cys Leu Ala Lys Arg Lys Ile Ala Gln Met Thr 65 70 75 80 Glu Glu Glu Gln Phe Ala Leu Ala Leu Lys Met Ser Glu Gln Glu Ala 85 90 95 Arg Glu Val Asn Ser Gln Glu Glu Glu Glu Glu Glu Leu Leu Arg Lys 100 105 110 Ala Ile Ala Glu Ser Leu Asn Ser Cys Arg Pro Ser Asp Ala Ser Ala 115 120 125 Thr Arg Ser Arg Pro Leu Ala Thr Gly Pro Ser Ser Gln Ser His Gln 130 135 140 Glu Lys Thr Thr Asp Ser Gly Leu Thr Glu Gly Ile Trp Gln Leu Val 145 150 155 160 Pro Pro Ser Leu Phe Lys Gly Ser His Ile Ser Gln Gly Asn Glu Ala 165 170 175 Glu Glu Arg Glu Glu Pro Trp Asp His Thr Glu Lys Thr Glu Glu Glu 180 185 190 Pro Val Ser Gly Ser Ser Gly Ser Trp Asp Gln Ser Ser Gln Pro Val 195 200 205 Phe Glu Asn Val Asn Val Lys Ser Phe Asp Arg Cys Thr Gly His Ser 210 215 220 Ala Glu His Thr Gln Cys Gly Lys Pro Gln Glu Ser Thr Gly Arg Gly 225 230 235 240 Ser Ala Phe Leu Lys Ala Val Gln Gly Ser Gly Asp Thr Ser Arg His 245 250 255 Cys Leu Pro Thr Leu Ala Asp Ala Lys Gly Leu Gln Asp Thr Gly Gly 260 265 270 Thr Val Asn Tyr Phe Trp Gly Ile Pro Phe Cys Pro Asp Gly Val Asp 275 280 285 Pro Asn Gln Tyr Thr Lys Val Ile Leu Cys Gln Leu Glu Val Tyr Gln 290 295 300 Lys Ser Leu Lys Met Ala Gln Arg Gln Leu Leu Asn Lys Lys Gly Phe 305 310 315 320 Gly Glu Pro Val Leu Pro Arg Pro Pro Ser Leu Ile Gln Asn Glu Cys 325 330 335 Gly Gln Gly Glu Gln Ala Ser Glu Lys Asn Gly Cys Ile Ser Glu Asp 340 345 350 Met Gly Asp Glu Asp Lys Glu Glu Arg Gln Glu Ser Arg Ala Ser Asp 355 360 365 Trp His Ser Lys Thr Lys Asp Phe Gln Glu Ser Ser Ile Lys Ser Leu 370 375 380 Lys Glu Lys Leu Leu Leu Glu Glu Glu Pro Thr Thr Ser His Gly Gln 385 390 395 400 Ser Ser Gln Gly Ile Val Glu Glu Thr Ser Glu Glu Gly Asn Ser Val 405 410 415 Pro Ala Ser Gln Ser Val Ala Ala Leu Thr Ser Lys Arg Ser Leu Val 420 425 430 Leu Met Pro Glu Ser Ser Ala Glu Glu Ile Thr Val Cys Pro Glu Thr 435 440 445 Gln Leu Ser Ser Ser Glu Thr Phe Asp Leu Glu Arg Glu Val Ser Pro 450 455 460 Gly Ser Arg Asp Ile Leu Asp Gly Val Arg Ile Ile Met Ala Asp Lys 465 470 475 480 Glu Val Gly Asn Lys Glu Asp Ala Glu Lys Glu Val Ala Ile Ser Thr 485 490 495 Phe Ser Ser Ser Asn Gln Val Ser Cys Pro Leu Cys Asp Gln Cys Phe 500 505 510 Pro Pro Thr Lys Ile Gly Arg His Ala Met Tyr Cys Asn Gly Leu Met 515 520 525 Glu Glu Asp Thr Val Leu Thr Arg Arg Gln Lys Glu Ala Lys Thr Lys 530 535 540 Ser Asp Ser Gly Thr Ala Ala Gln Thr Ser Leu Asp Ile Asp Lys Asn 545 550 555 560 Glu Lys Cys Tyr Leu Cys Lys Ser Leu Val Pro Phe Arg Glu Tyr Gln 565 570 575 Cys His Val Asp Ser Cys Leu Gln Leu Ala Lys Ala Asp Gln Gly Asp 580 585 590 Gly Pro Glu Gly Ser Gly Arg Ala Cys Ser Thr Val Glu Gly Lys Trp 595 600 605 Gln Gln Arg Leu Lys Asn Pro Lys Glu Lys Gly His Ser Glu Gly Arg 610 615 620 Leu Leu Ser Phe Leu Glu Gln Ser Glu His Lys Thr Ser Asp Ala Asp 625 630 635 640 Ile Lys Ser Ser Glu Thr Gly Ala Phe Arg Val Pro Ser Pro Gly Met 645 650 655 Glu Glu Ala Gly Cys Ser Arg Glu Met Gln Ser Ser Phe Thr Arg Arg 660 665 670 Asp Leu Asn Glu Ser Pro Val Lys Ser Phe Val Ser Ile Ser Glu Ala 675 680 685 Thr Asp Cys Leu Val Asp Phe Lys Lys Gln Val Thr Val Gln Pro Gly 690 695 700 Ser Arg Thr Arg Thr Lys Ala Gly Arg Gly Arg Arg Arg Lys Phe 705 710 715 9 415 PRT Homo sapiens 9 Met Ser Pro Glu Val Ala Leu Asn Arg Ile Ser Pro Met Leu Ser Pro 1 5 10 15 Phe Ile Ser Ser Val Val Arg Asn Gly Lys Val Gly Leu Asp Ala Thr 20 25 30 Asn Cys Leu Arg Ile Thr Asp Leu Lys Ser Gly Cys Thr Ser Leu Thr 35 40 45 Pro Gly Pro Asn Cys Asp Arg Phe Lys Leu His Ile Pro Tyr Ala Gly 50 55 60 Glu Thr Leu Lys Trp Asp Ile Ile Phe Asn Ala Gln Tyr Pro Glu Leu 65 70 75 80 Pro Pro Asp Phe Ile Phe Gly Glu Asp Ala Glu Phe Leu Pro Asp Pro 85 90 95 Ser Ala Leu Gln Asn Leu Ala Ser Trp Asn Pro Ser Asn Pro Glu Cys 100 105 110 Leu Leu Leu Val Val Lys Glu Leu Val Gln Gln Tyr His Gln Phe Gln 115 120 125 Cys Ser Arg Leu Arg Glu Ser Ser Arg Leu Met Phe Glu Tyr Gln Thr 130 135 140 Leu Leu Glu Glu Pro Gln Tyr Gly Glu Asn Met Glu Ile Tyr Ala Gly 145 150 155 160 Lys Lys Asn Asn Trp Thr Gly Glu Phe Ser Ala Arg Phe Leu Leu Lys 165 170 175 Leu Pro Val Asp Phe Ser Asn Ile Pro Thr Tyr Leu Leu Lys Asp Val 180 185 190 Asn Glu Asp Pro Gly Glu Asp Val Ala Leu Leu Ser Val Ser Phe Glu 195 200 205 Asp Thr Glu Ala Thr Gln Val Tyr Pro Lys Leu Tyr Leu Ser Pro Arg 210 215 220 Ile Glu His Ala Leu Gly Gly Ser Ser Ala Leu His Ile Pro Ala Phe 225 230 235 240 Pro Gly Gly Gly Cys Leu Ile Asp Tyr Val Pro Gln Val Cys His Leu 245 250 255 Leu Thr Asn Lys Val Gln Tyr Val Ile Gln Gly Tyr His Lys Arg Arg 260 265 270 Glu Tyr Ile Ala Ala Phe Leu Ser His Phe Gly Thr Gly Val Val Glu 275 280 285 Tyr Asp Ala Glu Gly Phe Thr Lys Leu Thr Leu Leu Leu Met Trp Lys 290 295 300 Asp Phe Cys Phe Leu Val His Ile Asp Leu Pro Leu Phe Phe Pro Arg 305 310 315 320 Asp Gln Pro Thr Leu Thr Phe Gln Ser Val Tyr His Phe Thr Asn Ser 325 330 335 Gly Gln Leu Tyr Ser Gln Ala Gln Lys Asn Tyr Pro Tyr Ser Pro Arg 340 345 350 Trp Asp Gly Asn Glu Met Ala Lys Arg Ala Lys Gly Cys Gln Gly Ser 355 360 365 Arg Asp Ala Cys Ser Pro Trp Glu Gln Val Leu Ala Phe Ala Val Ala 370 375 380 Lys Thr Gly Cys Lys Leu Leu Gln Pro Gln Arg Asn Trp Pro Ser Ser 385 390 395 400 Arg Gly Pro Pro Trp Arg Ala Ser Glu Gly Glu Arg Thr Ala Gln 405 410 415 10 316 PRT Homo sapiens 10 Met Ala Val Gln Val Val Gln Ala Val Gln Ala Val His Leu Glu Ser 1 5 10 15 Asp Ala Phe Leu Val Cys Leu Asn His Ala Leu Ser Thr Glu Lys Glu 20 25 30 Glu Val Met Gly Leu Cys Ile Gly Glu Leu Asn Asp Asp Thr Arg Ser 35 40 45 Asp Ser Lys Phe Ala Tyr Thr Gly Thr Glu Met Arg Thr Val Ala Glu 50 55 60 Lys Val Asp Ala Val Arg Ile Val His Ile His Ser Val Ile Ile Leu 65 70 75 80 Arg Arg Ser Asp Lys Arg Lys Asp Arg Val Glu Ile Ser Pro Glu Gln 85 90 95 Leu Ser Ala Ala Ser Thr Glu Ala Glu Arg Leu Ala Glu Leu Thr Gly 100 105 110 Arg Pro Met Arg Val Val Gly Trp Tyr His Ser His Pro His Ile Thr 115 120 125 Val Trp Pro Ser His Val Asp Val Arg Thr Gln Ala Met Tyr Gln Met 130 135 140 Met Asp Gln Gly Phe Val Gly Leu Ile Phe Ser Cys Phe Ile Glu Asp 145 150 155 160 Lys Asn Thr Lys Thr Gly Arg Val Leu Tyr Thr Cys Phe Gln Ser Ile 165 170 175 Gln Ala Gln Lys Ser Ser Glu Ser Leu His Gly Pro Arg Asp Phe Trp 180 185 190 Ser Ser Ser Gln His Ile Ser Ile Glu Gly Gln Lys Glu Glu Glu Arg 195 200 205 Tyr Glu Arg Ile Glu Ile Pro Ile His Ile Val Pro His Val Thr Ile 210 215 220 Gly Lys Val Cys Leu Glu Ser Ala Val Glu Leu Pro Lys Ile Leu Cys 225 230 235 240 Gln Glu Glu Gln Asp Ala Tyr Arg Arg Ile His Ser Leu Thr His Leu 245 250 255 Asp Ser Val Thr Lys Ile His Asn Gly Ser Val Phe Thr Lys Asn Leu 260 265 270 Cys Ser Gln Met Ser Ala Val Ser Gly Pro Leu Leu Gln Trp Leu Glu 275 280 285 Asp Arg Leu Glu Gln Asn Gln Gln His Leu Gln Glu Leu Gln Gln Glu 290 295 300 Lys Glu Glu Leu Met Gln Glu Leu Ser Ser Leu Glu 305 310 315 11 777 PRT Homo sapiens 11 Met Pro Asp Asn Arg Gln Pro Arg Asn Arg Gln Pro Arg Ile Arg Ser 1 5 10 15 Gly Asn Glu Pro Arg Ser Ala Pro Ala Met Glu Pro Asp Gly Arg Gly 20 25 30 Ala Trp Ala His Ser Arg Ala Ala Leu Asp Arg Leu Glu Lys Leu Leu 35 40 45 Arg Cys Ser Arg Cys Thr Asn Ile Leu Arg Glu Pro Val Cys Leu Gly 50 55 60 Gly Cys Glu His Ile Phe Cys Ser Asn Cys Val Ser Asp Cys Ile Gly 65 70 75 80 Thr Gly Cys Pro Val Cys Tyr Thr Pro Ala Trp Ile Gln Asp Leu Lys 85 90 95 Ile Asn Arg Gln Leu Asp Ser Met Ile Gln Leu Cys Ser Lys Leu Arg 100 105 110 Asn Leu Leu His Asp Asn Glu Leu Ser Asp Leu Lys Glu Asp Lys Pro 115 120 125 Arg Lys Ser Leu Phe Asn Asp Ala Gly Asn Lys Lys Asn Ser Ile Lys 130 135 140 Met Trp Phe Ser Pro Arg Ser Lys Lys Val Arg Tyr Val Val Ser Lys 145 150 155 160 Ala Ser Val Gln Thr Gln Pro Ala Ile Lys Lys Asp Ala Ser Ala Gln 165 170 175 Gln Asp Ser Tyr Glu Phe Val Ser Pro Ser Pro Pro Ala Asp Val Ser 180 185 190 Glu Arg Ala Lys Lys Ala Ser Ala Arg Ser Gly Lys Lys Gln Lys Lys 195 200 205 Lys Thr Leu Ala Glu Ile Asn Gln Lys Trp Asn Leu Glu Ala Glu Lys 210 215 220 Glu Asp Gly Glu Phe Asp Ser Lys Glu Glu Ser Lys Gln Lys Leu Val 225 230 235 240 Ser Phe Cys Ser Gln Pro Ser Val Ile Ser Ser Pro Gln Ile Asn Gly 245 250 255 Glu Ile Asp Leu Leu Ala Ser Gly Ser Leu Thr Glu Ser Glu Cys Phe 260 265 270 Gly Ser Leu Thr Glu Val Ser Leu Pro Leu Ala Glu Gln Ile Glu Ser 275 280 285 Pro Asp Thr Lys Ser Arg Asn Glu Val Val Thr Pro Glu Lys Val Cys 290 295 300 Lys Asn Tyr Leu Thr Ser Lys Lys Ser Leu Pro Leu Glu Asn Asn Gly 305 310 315 320 Lys Arg Gly His His Asn Arg Leu Ser Ser Pro Ile Ser Lys Arg Cys 325 330 335 Arg Thr Ser Ile Leu Ser Thr Ser Gly Asp Phe Val Lys Gln Thr Val 340 345 350 Pro Ser Glu Asn Ile Pro Leu Pro Glu Cys Ser Ser Pro Pro Ser Cys 355 360 365 Lys Arg Lys Val Gly Gly Thr Ser Gly Arg Lys Asn Ser Asn Met Ser 370 375 380 Asp Glu Phe Ile Ser Leu Ser Pro Gly Thr Pro Pro Ser Thr Leu Ser 385 390 395 400 Ser Ser Ser Tyr Arg Gln Val Met Ser Ser Pro Ser Ala Met Lys Leu 405 410 415 Leu Pro Asn Met Ala Val Lys Arg Asn His Arg Gly Glu Thr Leu Leu 420 425 430 His Ile Ala Ser Ile Lys Gly Asp Ile Pro Ser Val Glu Tyr Leu Leu 435 440 445 Gln Asn Gly Ser Asp Pro Asn Val Lys Asp His Ala Gly Trp Thr Pro 450 455 460 Leu His Glu Ala Cys Asn His Gly His Leu Lys Val Val Glu Leu Leu 465 470 475 480 Leu Gln His Lys Ala Leu Val Asn Thr Thr Gly Tyr Gln Asn Asp Ser 485 490 495 Pro Leu His Asp Ala Ala Lys Asn Gly His Val Asp Ile Val Lys Leu 500 505 510 Leu Leu Ser Tyr Gly Ala Ser Arg Asn Ala Val Asn Ile Phe Gly Leu 515 520 525 Arg Pro Val Asp Tyr Thr Asp Asp Glu Ser Met Lys Ser Leu Leu Leu 530 535 540 Leu Pro Glu Lys Asn Glu Ser Ser Ser Ala Ser His Cys Ser Val Met 545 550 555 560 Asn Thr Gly Gln Arg Arg Asp Gly Pro Leu Val Leu Ile Gly Ser Gly 565 570 575 Leu Ser Ser Glu Gln Gln Lys Met Leu Ser Glu Leu Ala Val Ile Leu 580 585 590 Lys Ala Lys Lys Tyr Thr Glu Phe Asp Ser Thr Val Thr His Val Val 595 600 605 Val Pro Gly Asp Ala Val Gln Ser Thr Leu Lys Cys Met Leu Gly Ile 610 615 620 Leu Asn Gly Cys Trp Ile Leu Lys Phe Glu Trp Val Lys Ala Cys Leu 625 630 635 640 Arg Arg Lys Val Cys Glu Gln Glu Glu Lys Tyr Glu Ile Pro Glu Gly 645 650 655 Pro Arg Arg Ser Arg Leu Asn Arg Glu Gln Leu Leu Pro Lys Leu Phe 660 665 670 Asp Gly Cys Tyr Phe Tyr Leu Trp Gly Thr Phe Lys His His Pro Lys 675 680 685 Asp Asn Leu Ile Lys Leu Val Thr Ala Gly Gly Gly Gln Ile Leu Ser 690 695 700 Arg Lys Pro Lys Pro Asp Ser Asp Val Thr Gln Thr Ile Asn Thr Val 705 710 715 720 Ala Tyr His Ala Arg Pro Asp Ser Asp Gln Arg Phe Cys Thr Gln Tyr 725 730 735 Ile Ile Tyr Glu Asp Leu Cys Asn Tyr His Pro Glu Arg Val Arg Gln 740 745 750 Gly Lys Val Trp Lys Ala Pro Ser Ser Trp Phe Ile Asp Cys Val Met 755 760 765 Ser Phe Glu Leu Leu Pro Leu Asp Ser 770 775 12 10987 DNA Homo sapiens 12 ggtggcgcga gcttctgaaa ctaggcggca gaggcggagc cgctgtggca ctgctgcgcc 60 tctgctgcgc ctcgggtgtc ttttgcggcg gtgggtcgcc gccgggagaa gcgtgagggg 120 acagatttgt gaccggcgcg gtttttgtca gcttactccg gccaaaaaag aactgcacct 180 ctggagcgga cttatttacc aagcattgga ggaatatcgt aggtaaaaat gcctattgga 240 tccaaagaga ggccaacatt ttttgaaatt tttaagacac gctgcaacaa agcagattta 300 ggaccaataa gtcttaattg gtttgaagaa ctttcttcag aagctccacc ctataattct 360 gaacctgcag aagaatctga acataaaaac aacaattacg aaccaaacct atttaaaact 420 ccacaaagga aaccatctta taatcagctg gcttcaactc caataatatt caaagagcaa 480 gggctgactc tgccgctgta ccaatctcct gtaaaagaat tagataaatt caaattagac 540 ttaggaagga atgttcccaa tagtagacat aaaagtcttc gcacagtgaa aactaaaatg 600 gatcaagcag atgatgtttc ctgtccactt ctaaattctt gtcttagtga aagtcctgtt 660 gttctacaat gtacacatgt aacaccacaa agagataagt cagtggtatg tgggagtttg 720 tttcatacac caaagtttgt gaagggtcgt cagacaccaa aacatatttc tgaaagtcta 780 ggagctgagg tggatcctga tatgtcttgg tcaagttctt tagctacacc acccaccctt 840 agttctactg tgctcatagt cagaaatgaa gaagcatctg aaactgtatt tcctcatgat 900 actactgcta atgtgaaaag ctatttttcc aatcatgatg aaagtctgaa gaaaaatgat 960 agatttatcg cttctgtgac agacagtgaa aacacaaatc aaagagaagc tgcaagtcat 1020 ggatttggaa aaacatcagg gaattcattt aaagtaaata gctgcaaaga ccacattgga 1080 aagtcaatgc caaatgtcct agaagatgaa gtatatgaaa cagttgtaga tacctctgaa 1140 gaagatagtt tttcattatg tttttctaaa tgtagaacaa aaaatctaca aaaagtaaga 1200 actagcaaga ctaggaaaaa aattttccat gaagcaaacg ctgatgaatg tgaaaaatct 1260 aaaaaccaag tgaaagaaaa atactcattt gtatctgaag tggaaccaaa tgatactgat 1320 ccattagatt caaatgtagc acatcagaag ccctttgaga gtggaagtga caaaatctcc 1380 aaggaagttg taccgtcttt ggcctgtgaa tggtctcaac taaccctttc aggtctaaat 1440 ggagcccaga tggagaaaat acccctattg catatttctt catgtgacca aaatatttca 1500 gaaaaagacc tattagacac agagaacaaa agaaagaaag attttcttac ttcagagaat 1560 tctttgccac gtatttctag cctaccaaaa tcagagaagc cattaaatga ggaaacagtg 1620 gtaaataaga gagatgaaga gcagcatctt gaatctcata cagactgcat tcttgcagta 1680 aagcaggcaa tatctggaac ttctccagtg gcttcttcat ttcagggtat caaaaagtct 1740 atattcagaa taagagaatc acctaaagag actttcaatg caagtttttc aggtcatatg 1800 actgatccaa actttaaaaa agaaactgaa gcctctgaaa gtggactgga aatacatact 1860 gtttgctcac agaaggagga ctccttatgt ccaaatttaa ttgataatgg aagctggcca 1920 gccaccacca cacagaattc tgtagctttg aagaatgcag gtttaatatc cactttgaaa 1980 aagaaaacaa ataagtttat ttatgctata catgatgaaa cattttataa aggaaaaaaa 2040 ataccgaaag accaaaaatc agaactaatt aactgttcag cccagtttga agcaaatgct 2100 tttgaagcac cacttacatt tgcaaatgct gattcaggtt tattgcattc ttctgtgaaa 2160 agaagctgtt cacagaatga ttctgaagaa ccaactttgt ccttaactag ctcttttggg 2220 acaattctga ggaaatgttc tagaaatgaa acatgttcta ataatacagt aatctctcag 2280 gatcttgatt ataaagaagc aaaatgtaat aaggaaaaac tacagttatt tattacccca 2340 gaagctgatt ctctgtcatg cctgcaggaa ggacagtgtg aaaatgatcc aaaaagcaaa 2400 aaagtttcag atataaaaga agaggtcttg gctgcagcat gtcacccagt acaacattca 2460 aaagtggaat acagtgatac tgactttcaa tcccagaaaa gtcttttata tgatcatgaa 2520 aatgccagca ctcttatttt aactcctact tccaaggatg ttctgtcaaa cctagtcatg 2580 atttctagag gcaaagaatc atacaaaatg tcagacaagc tcaaaggtaa caattatgaa 2640 tctgatgttg aattaaccaa aaatattccc atggaaaaga atcaagatgt atgtgcttta 2700 aatgaaaatt ataaaaacgt tgagctgttg ccacctgaaa aatacatgag agtagcatca 2760 ccttcaagaa aggtacaatt caaccaaaac acaaatctaa gagtaatcca aaaaaatcaa 2820 gaagaaacta cttcaatttc aaaaataact gtcaatccag actctgaaga acttttctca 2880 gacaatgaga ataattttgt cttccaagta gctaatgaaa ggaataatct tgctttagga 2940 aatactaagg aacttcatga aacagacttg acttgtgtaa acgaacccat tttcaagaac 3000 tctaccatgg ttttatatgg agacacaggt gataaacaag caacccaagt gtcaattaaa 3060 aaagatttgg tttatgttct tgcagaggag aacaaaaata gtgtaaagca gcatataaaa 3120 atgactctag gtcaagattt aaaatcggac atctccttga atatagataa aataccagaa 3180 aaaaataatg attacatgaa caaatgggca ggactcttag gtccaatttc aaatcacagt 3240 tttggaggta gcttcagaac agcttcaaat aaggaaatca agctctctga acataacatt 3300 aagaagagca aaatgttctt caaagatatt gaagaacaat atcctactag tttagcttgt 3360 gttgaaattg taaatacctt ggcattagat aatcaaaaga aactgagcaa gcctcagtca 3420 attaatactg tatctgcaca tttacagagt agtgtagttg tttctgattg taaaaatagt 3480 catataaccc ctcagatgtt attttccaag caggatttta attcaaacca taatttaaca 3540 cctagccaaa aggcagaaat tacagaactt tctactatat tagaagaatc aggaagtcag 3600 tttgaattta ctcagtttag aaaaccaagc tacatattgc agaagagtac atttgaagtg 3660 cctgaaaacc agatgactat cttaaagacc acttctgagg aatgcagaga tgctgatctt 3720 catgtcataa tgaatgcccc atcgattggt caggtagaca gcagcaagca atttgaaggt 3780 acagttgaaa ttaaacggaa gtttgctggc ctgttgaaaa atgactgtaa caaaagtgct 3840 tctggttatt taacagatga aaatgaagtg gggtttaggg gcttttattc tgctcatggc 3900 acaaaactga atgtttctac tgaagctctg caaaaagctg tgaaactgtt tagtgatatt 3960 gagaatatta gtgaggaaac ttctgcagag gtacatccaa taagtttatc ttcaagtaaa 4020 tgtcatgatt ctgttgtttc aatgtttaag atagaaaatc ataatgataa aactgtaagt 4080 gaaaaaaata ataaatgcca actgatatta caaaataata ttgaaatgac tactggcact 4140 tttgttgaag aaattactga aaattacaag agaaatactg aaaatgaaga taacaaatat 4200 actgctgcca gtagaaattc tcataactta gaatttgatg gcagtgattc aagtaaaaat 4260 gatactgttt gtattcataa agatgaaacg gacttgctat ttactgatca gcacaacata 4320 tgtcttaaat tatctggcca gtttatgaag gagggaaaca ctcagattaa agaagatttg 4380 tcagatttaa cttttttgga agttgcgaaa gctcaagaag catgtcatgg taatacttca 4440 aataaagaac agttaactgc tactaaaacg gagcaaaata taaaagattt tgagacttct 4500 gatacatttt ttcagactgc aagtgggaaa aatattagtg tcgccaaaga gtcatttaat 4560 aaaattgtaa atttctttga tcagaaacca gaagaattgc ataacttttc cttaaattct 4620 gaattacatt ctgacataag aaagaacaaa atggacattc taagttatga ggaaacagac 4680 atagttaaac acaaaatact gaaagaaagt gtcccagttg gtactggaaa tcaactagtg 4740 accttccagg gacaacccga acgtgatgaa aagatcaaag aacctactct gttgggtttt 4800 catacagcta gcgggaaaaa agttaaaatt gcaaaggaat ctttggacaa agtgaaaaac 4860 ctttttgatg aaaaagagca aggtactagt gaaatcacca gttttagcca tcaatgggca 4920 aagaccctaa agtacagaga ggcctgtaaa gaccttgaat tagcatgtga gaccattgag 4980 atcacagctg ccccaaagtg taaagaaatg cagaattctc tcaataatga taaaaacctt 5040 gtttctattg agactgtggt gccacctaag ctcttaagtg ataatttatg tagacaaact 5100 gaaaatctca aaacatcaaa aagtatcttt ttgaaagtta aagtacatga aaatgtagaa 5160 aaagaaacag caaaaagtcc tgcaacttgt tacacaaatc agtcccctta ttcagtcatt 5220 gaaaattcag ccttagcttt ttacacaagt tgtagtagaa aaacttctgt gagtcagact 5280 tcattacttg aagcaaaaaa atggcttaga gaaggaatat ttgatggtca accagaaaga 5340 ataaatactg cagattatgt aggaaattat ttgtatgaaa ataattcaaa cagtactata 5400 gctgaaaatg acaaaaatca tctctccgaa aaacaagata cttatttaag taacagtagc 5460 atgtctaaca gctattccta ccattctgat gaggtatata atgattcagg atatctctca 5520 aaaaataaac ttgattctgg tattgagcca gtattgaaga atgttgaaga tcaaaaaaac 5580 actagttttt ccaaagtaat atccaatgta aaagatgcaa atgcataccc acaaactgta 5640 aatgaagata tttgcgttga ggaacttgtg actagctctt caccctgcaa aaataaaaat 5700 gcagccatta aattgtccat atctaatagt aataattttg aggtagggcc acctgcattt 5760 aggatagcca gtggtaaaat cgtttgtgtt tcacatgaaa caattaaaaa agtgaaagac 5820 atatttacag acagtttcag taaagtaatt aaggaaaaca acgagaataa atcaaaaatt 5880 tgccaaacga aaattatggc aggttgttac gaggcattgg atgattcaga ggatattctt 5940 cataactctc tagataatga tgaatgtagc acgcattcac ataaggtttt tgctgacatt 6000 cagagtgaag aaattttaca acataaccaa aatatgtctg gattggagaa agtttctaaa 6060 atatcacctt gtgatgttag tttggaaact tcagatatat gtaaatgtag tatagggaag 6120 cttcataagt cagtctcatc tgcaaatact tgtgggattt ttagcacagc aagtggaaaa 6180 tctgtccagg tatcagatgc ttcattacaa aacgcaagac aagtgttttc tgaaatagaa 6240 gatagtacca agcaagtctt ttccaaagta ttgtttaaaa gtaacgaaca ttcagaccag 6300 ctcacaagag aagaaaatac tgctatacgt actccagaac atttaatatc ccaaaaaggc 6360 ttttcatata atgtggtaaa ttcatctgct ttctctggat ttagtacagc aagtggaaag 6420 caagtttcca ttttagaaag ttccttacac aaagttaagg gagtgttaga ggaatttgat 6480 ttaatcagaa ctgagcatag tcttcactat tcacctacgt ctagacaaaa tgtatcaaaa 6540 atacttcctc gtgttgataa gagaaaccca gagcactgtg taaactcaga aatggaaaaa 6600 acctgcagta aagaatttaa attatcaaat aacttaaatg ttgaaggtgg ttcttcagaa 6660 aataatcact ctattaaagt ttctccatat ctctctcaat ttcaacaaga caaacaacag 6720 ttggtattag gaaccaaagt ctcacttgtt gagaacattc atgttttggg aaaagaacag 6780 gcttcaccta aaaacgtaaa aatggaaatt ggtaaaactg aaactttttc tgatgttcct 6840 gtgaaaacaa atatagaagt ttgttctact tactccaaag attcagaaaa ctactttgaa 6900 acagaagcag tagaaattgc taaagctttt atggaagatg atgaactgac agattctaaa 6960 ctgccaagtc atgccacaca ttctcttttt acatgtcccg aaaatgagga aatggttttg 7020 tcaaattcaa gaattggaaa aagaagagga gagcccctta tcttagtggg agaaccctca 7080 atcaaaagaa acttattaaa tgaatttgac aggataatag aaaatcaaga aaaatcctta 7140 aaggcttcaa aaagcactcc agatggcaca ataaaagatc gaagattgtt tatgcatcat 7200 gtttctttag agccgattac ctgtgtaccc tttcgcacaa ctaaggaacg tcaagagata 7260 cagaatccaa attttaccgc acctggtcaa gaatttctgt ctaaatctca tttgtatgaa 7320 catctgactt tggaaaaatc ttcaagcaat ttagcagttt caggacatcc attttatcaa 7380 gtttctgcta caagaaatga aaaaatgaga cacttgatta ctacaggcag accaaccaaa 7440 gtctttgttc caccttttaa aactaaatca cattttcaca gagttgaaca gtgtgttagg 7500 aatattaact tggaggaaaa cagacaaaag caaaacattg atggacatgg ctctgatgat 7560 agtaaaaata agattaatga caatgagatt catcagttta acaaaaacaa ctccaatcaa 7620 gcagcagctg taactttcac aaagtgtgaa gaagaacctt tagatttaat tacaagtctt 7680 cagaatgcca gagatataca ggatatgcga attaagaaga aacaaaggca acgcgtcttt 7740 ccacagccag gcagtctgta tcttgcaaaa acatccactc tgcctcgaat ctctctgaaa 7800 gcagcagtag gaggccaagt tccctctgcg tgttctcata aacagctgta tacgtatggc 7860 gtttctaaac attgcataaa aattaacagc aaaaatgcag agtcttttca gtttcacact 7920 gaagattatt ttggtaagga aagtttatgg actggaaaag gaatacagtt ggctgatggt 7980 ggatggctca taccctccaa tgatggaaag gctggaaaag aagaatttta tagggctctg 8040 tgtgacactc caggtgtgga tccaaagctt atttctagaa tttgggttta taatcactat 8100 agatggatca tatggaaact ggcagctatg gaatgtgcct ttcctaagga atttgctaat 8160 agatgcctaa gcccagaaag ggtgcttctt caactaaaat acagatatga tacggaaatt 8220 gatagaagca gaagatcggc tataaaaaag ataatggaaa gggatgacac agctgcaaaa 8280 acacttgttc tctgtgtttc tgacataatt tcattgagcg caaatatatc tgaaacttct 8340 agcaataaaa ctagtagtgc agatacccaa aaagtggcca ttattgaact tacagatggg 8400 tggtatgctg ttaaggccca gttagatcct cccctcttag ctgtcttaaa gaatggcaga 8460 ctgacagttg gtcagaagat tattcttcat ggagcagaac tggtgggctc tcctgatgcc 8520 tgtacacctc ttgaagcccc agaatctctt atgttaaaga tttctgctaa cagtactcgg 8580 cctgctcgct ggtataccaa acttggattc tttcctgacc ctagaccttt tcctctgccc 8640 ttatcatcgc ttttcagtga tggaggaaat gttggttgtg ttgatgtaat tattcaaaga 8700 gcatacccta tacagtggat ggagaagaca tcatctggat tatacatatt tcgcaatgaa 8760 agagaggaag aaaaggaagc agcaaaatat gtggaggccc aacaaaagag actagaagcc 8820 ttattcacta aaattcagga ggaatttgaa gaacatgaag aaaacacaac aaaaccatat 8880 ttaccatcac gtgcactaac aagacagcaa gttcgtgctt tgcaagatgg tgcagagctt 8940 tatgaagcag tgaagaatgc agcagaccca gcttaccttg agggttattt cagtgaagag 9000 cagttaagag ccttgaataa tcacaggcaa atgttgaatg ataagaaaca agctcagatc 9060 cagttggaaa ttaggaaggc catggaatct gctgaacaaa aggaacaagg tttatcaagg 9120 gatgtcacaa ccgtgtggaa gttgcgtatt gtaagctatt caaaaaaaga aaaagattca 9180 gttatactga gtatttggcg tccatcatca gatttatatt ctctgttaac agaaggaaag 9240 agatacagaa tttatcatct tgcaacttca aaatctaaaa gtaaatctga aagagctaac 9300 atacagttag cagcgacaaa aaaaactcag tatcaacaac taccggtttc agatgaaatt 9360 ttatttcaga tttaccagcc acgggagccc cttcacttca gcaaattttt agatccagac 9420 tttcagccat cttgttctga ggtggaccta ataggatttg tcgtttctgt tgtgaaaaaa 9480 acaggacttg cccctttcgt ctatttgtca gacgaatgtt acaatttact ggcaataaag 9540 ttttggatag accttaatga ggacattatt aagcctcata tgttaattgc tgcaagcaac 9600 ctccagtggc gaccagaatc caaatcaggc cttcttactt tatttgctgg agatttttct 9660 gtgttttctg ctagtccaaa agagggccac tttcaagaga cattcaacaa aatgaaaaat 9720 actgttgaga atattgacat actttgcaat gaagcagaaa acaagcttat gcatatactg 9780 catgcaaatg atcccaagtg gtccacccca actaaagact gtacttcagg gccgtacact 9840 gctcaaatca ttcctggtac aggaaacaag cttctgatgt cttctcctaa ttgtgagata 9900 tattatcaaa gtcctttatc actttgtatg gccaaaagga agtctgtttc cacacctgtc 9960 tcagcccaga tgacttcaaa gtcttgtaaa ggggagaaag agattgatga ccaaaagaac 10020 tgcaaaaaga gaagagcctt ggatttcttg agtagactgc ctttacctcc acctgttagt 10080 cccatttgta catttgtttc tccggctgca cagaaggcat ttcagccacc aaggagttgt 10140 ggcaccaaat acgaaacacc cataaagaaa aaagaactga attctcctca gatgactcca 10200 tttaaaaaat tcaatgaaat ttctcttttg gaaagtaatt caatagctga cgaagaactt 10260 gcattgataa atacccaagc tcttttgtct ggttcaacag gagaaaaaca atttatatct 10320 gtcagtgaat ccactaggac tgctcccacc agttcagaag attatctcag actgaaacga 10380 cgttgtacta catctctgat caaagaacag gagagttccc aggccagtac ggaagaatgt 10440 gagaaaaata agcaggacac aattacaact aaaaaatata tctaagcatt tgcaaaggcg 10500 acaataaatt attgacgctt aacctttcca gtttataaga ctggaatata atttcaaacc 10560 acacattagt acttatgttg cacaatgaga aaagaaatta gtttcaaatt tacctcagcg 10620 tttgtgtatc gggcaaaaat cgttttgccc gattccgtat tggtatactt ttgcttcagt 10680 tgcatatctt aaaactaaat gtaatttatt aactaatcaa gaaaaacatc tttggctgag 10740 ctcggtggct catgcctgta atcccaacac tttgagaagc tgaggtggga ggagtgcttg 10800 aggccaggag ttcaagacca gcctgggcaa catagggaga cccccatctt tacgaagaaa 10860 aaaaaaaagg ggaaaagaaa atcttttaaa tctttggatt tgatcactac aagtattatt 10920 ttacaatcaa caaaatggtc atccaaactc aaacttgaga aaatatcttg ctttcaaatt 10980 gacacta 10987 13 5711 DNA Homo sapiens 13 agctcgctga gacttcctgg accccgcacc aggctgtggg gtttctcaga taactgggcc 60 cctgcgctca ggaggccttc accctctgct ctgggtaaag ttcattggaa cagaaagaaa 120 tggatttatc tgctcttcgc gttgaagaag tacaaaatgt cattaatgct atgcagaaaa 180 tcttagagtg tcccatctgt ctggagttga tcaaggaacc tgtctccaca aagtgtgacc 240 acatattttg caaattttgc atgctgaaac ttctcaacca gaagaaaggg ccttcacagt 300 gtcctttatg taagaatgat ataaccaaaa ggagcctaca agaaagtacg agatttagtc 360 aacttgttga agagctattg aaaatcattt gtgcttttca gcttgacaca ggtttggagt 420 atgcaaacag ctataatttt gcaaaaaagg aaaataactc tcctgaacat ctaaaagatg 480 aagtttctat catccaaagt atgggctaca gaaaccgtgc caaaagactt ctacagagtg 540 aacccgaaaa tccttccttg caggaaacca gtctcagtgt ccaactctct aaccttggaa 600 ctgtgagaac tctgaggaca aagcagcgga tacaacctca aaagacgtct gtctacattg 660 aattgggatc tgattcttct gaagataccg ttaataaggc aacttattgc agtgtgggag 720 atcaagaatt gttacaaatc acccctcaag gaaccaggga tgaaatcagt ttggattctg 780 caaaaaaggc tgcttgtgaa ttttctgaga cggatgtaac aaatactgaa catcatcaac 840 ccagtaataa tgatttgaac accactgaga agcgtgcagc tgagaggcat ccagaaaagt 900 atcagggtag ttctgtttca aacttgcatg tggagccatg tggcacaaat actcatgcca 960 gctcattaca gcatgagaac agcagtttat tactcactaa agacagaatg aatgtagaaa 1020 aggctgaatt ctgtaataaa agcaaacagc ctggcttagc aaggagccaa cataacagat 1080 gggctggaag taaggaaaca tgtaatgata ggcggactcc cagcacagaa aaaaaggtag 1140 atctgaatgc tgatcccctg tgtgagagaa aagaatggaa taagcagaaa ctgccatgct 1200 cagagaatcc tagagatact gaagatgttc cttggataac actaaatagc agcattcaga 1260 aagttaatga gtggttttcc agaagtgatg aactgttagg ttctgatgac tcacatgatg 1320 gggagtctga atcaaatgcc aaagtagctg atgtattgga cgttctaaat gaggtagatg 1380 aatattctgg ttcttcagag aaaatagact tactggccag tgatcctcat gaggctttaa 1440 tatgtaaaag tgaaagagtt cactccaaat cagtagagag taatattgaa gacaaaatat 1500 ttgggaaaac ctatcggaag aaggcaagcc tccccaactt aagccatgta actgaaaatc 1560 taattatagg agcatttgtt actgagccac agataataca agagcgtccc ctcacaaata 1620 aattaaagcg taaaaggaga cctacatcag gccttcatcc tgaggatttt atcaagaaag 1680 cagatttggc agttcaaaag actcctgaaa tgataaatca gggaactaac caaacggagc 1740 agaatggtca agtgatgaat attactaata gtggtcatga gaataaaaca aaaggtgatt 1800 ctattcagaa tgagaaaaat cctaacccaa tagaatcact cgaaaaagaa tctgctttca 1860 aaacgaaagc tgaacctata agcagcagta taagcaatat ggaactcgaa ttaaatatcc 1920 acaattcaaa agcacctaaa aagaataggc tgaggaggaa gtcttctacc aggcatattc 1980 atgcgcttga actagtagtc agtagaaatc taagcccacc taattgtact gaattgcaaa 2040 ttgatagttg ttctagcagt gaagagataa agaaaaaaaa gtacaaccaa atgccagtca 2100 ggcacagcag aaacctacaa ctcatggaag gtaaagaacc tgcaactgga gccaagaaga 2160 gtaacaagcc aaatgaacag acaagtaaaa gacatgacag cgatactttc ccagagctga 2220 agttaacaaa tgcacctggt tcttttacta agtgttcaaa taccagtgaa cttaaagaat 2280 ttgtcaatcc tagccttcca agagaagaaa aagaagagaa actagaaaca gttaaagtgt 2340 ctaataatgc tgaagacccc aaagatctca tgttaagtgg agaaagggtt ttgcaaactg 2400 aaagatctgt agagagtagc agtatttcat tggtacctgg tactgattat ggcactcagg 2460 aaagtatctc gttactggaa gttagcactc tagggaaggc aaaaacagaa ccaaataaat 2520 gtgtgagtca gtgtgcagca tttgaaaacc ccaagggact aattcatggt tgttccaaag 2580 ataatagaaa tgacacagaa ggctttaagt atccattggg acatgaagtt aaccacagtc 2640 gggaaacaag catagaaatg gaagaaagtg aacttgatgc tcagtatttg cagaatacat 2700 tcaaggtttc aaagcgccag tcatttgctc cgttttcaaa tccaggaaat gcagaagagg 2760 aatgtgcaac attctctgcc cactctgggt ccttaaagaa acaaagtcca aaagtcactt 2820 ttgaatgtga acaaaaggaa gaaaatcaag gaaagaatga gtctaatatc aagcctgtac 2880 agacagttaa tatcactgca ggctttcctg tggttggtca gaaagataag ccagttgata 2940 atgccaaatg tagtatcaaa ggaggctcta ggttttgtct atcatctcag ttcagaggca 3000 acgaaactgg actcattact ccaaataaac atggactttt acaaaaccca tatcgtatac 3060 caccactttt tcccatcaag tcatttgtta aaactaaatg taagaaaaat ctgctagagg 3120 aaaactttga ggaacattca atgtcacctg aaagagaaat gggaaatgag aacattccaa 3180 gtacagtgag cacaattagc cgtaataaca ttagagaaaa tgtttttaaa gaagccagct 3240 caagcaatat taatgaagta ggttccagta ctaatgaagt gggctccagt attaatgaaa 3300 taggttccag tgatgaaaac attcaagcag aactaggtag aaacagaggg ccaaaattga 3360 atgctatgct tagattaggg gttttgcaac ctgaggtcta taaacaaagt cttcctggaa 3420 gtaattgtaa gcatcctgaa ataaaaaagc aagaatatga agaagtagtt cagactgtta 3480 atacagattt ctctccatat ctgatttcag ataacttaga acagcctatg ggaagtagtc 3540 atgcatctca ggtttgttct gagacacctg atgacctgtt agatgatggt gaaataaagg 3600 aagatactag ttttgctgaa aatgacatta aggaaagttc tgctgttttt agcaaaagcg 3660 tccagaaagg agagcttagc aggagtccta gccctttcac ccatacacat ttggctcagg 3720 gttaccgaag aggggccaag aaattagagt cctcagaaga gaacttatct agtgaggatg 3780 aagagcttcc ctgcttccaa cacttgttat ttggtaaagt aaacaatata ccttctcagt 3840 ctactaggca tagcaccgtt gctaccgagt gtctgtctaa gaacacagag gagaatttat 3900 tatcattgaa gaatagctta aatgactgca gtaaccaggt aatattggca aaggcatctc 3960 aggaacatca ccttagtgag gaaacaaaat gttctgctag cttgttttct tcacagtgca 4020 gtgaattgga agacttgact gcaaatacaa acacccagga tcctttcttg attggttctt 4080 ccaaacaaat gaggcatcag tctgaaagcc agggagttgg tctgagtgac aaggaattgg 4140 tttcagatga tgaagaaaga ggaacgggct tggaagaaaa taatcaagaa gagcaaagca 4200 tggattcaaa cttaggtgaa gcagcatctg ggtgtgagag tgaaacaagc gtctctgaag 4260 actgctcagg gctatcctct cagagtgaca ttttaaccac tcagcagagg gataccatgc 4320 aacataacct gataaagctc cagcaggaaa tggctgaact agaagctgtg ttagaacagc 4380 atgggagcca gccttctaac agctaccctt ccatcataag tgactcttct gcccttgagg 4440 acctgcgaaa tccagaacaa agcacatcag aaaaagcagt attaacttca cagaaaagta 4500 gtgaataccc tataagccag aatccagaag gcctttctgc tgacaagttt gaggtgtctg 4560 cagatagttc taccagtaaa aataaagaac caggagtgga aaggtcatcc ccttctaaat 4620 gcccatcatt agatgatagg tggtacatgc acagttgctc tgggagtctt cagaatagaa 4680 actacccatc tcaagaggag ctcattaagg ttgttgatgt ggaggagcaa cagctggaag 4740 agtctgggcc acacgatttg acggaaacat cttacttgcc aaggcaagat ctagagggaa 4800 ccccttacct ggaatctgga atcagcctct tctctgatga ccctgaatct gatccttctg 4860 aagacagagc cccagagtca gctcgtgttg gcaacatacc atcttcaacc tctgcattga 4920 aagttcccca attgaaagtt gcagaatctg cccagagtcc agctgctgct catactactg 4980 atactgctgg gtataatgca atggaagaaa gtgtgagcag ggagaagcca gaattgacag 5040 cttcaacaga aagggtcaac aaaagaatgt ccatggtggt gtctggcctg accccagaag 5100 aatttatgct cgtgtacaag tttgccagaa aacaccacat cactttaact aatctaatta 5160 ctgaagagac tactcatgtt gttatgaaaa cagatgctga gtttgtgtgt gaacggacac 5220 tgaaatattt tctaggaatt gcgggaggaa aatgggtagt tagctatttc tgggtgaccc 5280 agtctattaa agaaagaaaa atgctgaatg agcatgattt tgaagtcaga ggagatgtgg 5340 tcaatggaag aaaccaccaa ggtccaaagc gagcaagaga atcccaggac agaaagatct 5400 tcagggggct agaaatctgt tgctatgggc ccttcaccaa catgcccaca gatcaactgg 5460 aatggatggt acagctgtgt ggtgcttctg tggtgaagga gctttcatca ttcacccttg 5520 gcacaggtgt ccacccaatt gtggttgtgc agccagatgc ctggacagag gacaatggct 5580 tccatgcaat tgggcagatg tgtgaggcac ctgtggtgac ccgagagtgg gtgttggaca 5640 gtgtagcact ctaccagtgc caggagctgg acacctacct gataccccag atcccccaca 5700 gccactactg a 5711 14 2229 DNA Homo sapiens 14 ccgcgcgcag cggccagaga ccgagcccta aggagagtgc ggcgcttccc gaggcgtgca 60 gctgggaact gcaactcatc tgggttgtgc gcagaaggct ggggcaagcg agtagagaag 120 tggagcgtaa gccaggggcg ttgggggccg tgcgggtcgg gcgcgtgcca cgcccgcggg 180 gtgaagtcgg agcgcggggc ctgctggaga gaggagcgct gcggaccgag taatggcaat 240 gcagatgcag cttgaagcaa atgcagatac ttcagtggaa gaagaaagct ttggcccaca 300 acccatttca cggttagagc agtgtggcat aaatgccaac gatgtgaaga aattggaaga 360 agctggattc catactgtgg aggctgttgc ctatgcgcca aagaaggagc taataaatat 420 taagggaatt agtgaagcca aagctgataa aattctggct gaggcagcta aattagttcc 480 aatgggtttc accactgcaa ctgaattcca ccaaaggcgg tcagagatca tacagattac 540 tactggctcc aaagagcttg acaaactact tcaaggtgga attgagactg gatctatcac 600 agaaatgttt ggagaattcc gaactgggaa gacccagatc tgtcatacgc tagctgtcac 660 ctgccagctt cccattgacc ggggtggagg tgaaggaaag gccatgtaca ttgacactga 720 gggtaccttt aggccagaac ggctgctggc agtggctgag aggtatggtc tctctggcag 780 tgatgtcctg gataatgtag catatgctcg agcgttcaac acagaccacc agacccagct 840 cctttatcaa gcatcagcca tgatggtaga atctaggtat gcactgctta ttgtagacag 900 tgccaccgcc ctttacagaa cagactactc gggtcgaggt gagctttcag ccaggcagat 960 gcacttggcc aggtttctgc ggatgcttct gcgactcgct gatgagtttg gtgtagcagt 1020 ggtaatcact aatcaggtgg tagctcaagt ggatggagca gcgatgtttg ctgctgatcc 1080 caaaaaacct attggaggaa atatcatcgc ccatgcatca acaaccagat tgtatctgag 1140 gaaaggaaga ggggaaacca gaatctgcaa aatctacgac tctccctgtc ttcctgaagc 1200 tgaagctatg ttcgccatta atgcagatgg agtgggagat gccaaagact gaatcattgg 1260 gtttttcctc tgttaaaaac cttaagtgct gcagcctaat gagagtgcac tgctccctgg 1320 ggttctctac aggcctcttc ctgttgtgac tgccaggata aagcttccgg gaaaacagct 1380 attatatcag cttttctgat ggtataaaca ggagacaggt cagtagtcac aaactgatct 1440 aaaatgttta ttccttctgt agtgtattaa tctctgtgtg ttttctttgg ttttggagga 1500 ggggtatgaa gtatctttga catggtgcct taggaatgac ttgggtttaa caagctgtct 1560 actggacaat cttatgtttc caagagaact aaagctggag agacctgacc cttctctcac 1620 ttctaaatta atggtaaaat aaaatgcctc agctatgtag caaagggaat gggtctgcac 1680 agattctttt tttctgtcag taaaactctc aagcaggttt ttaagttgtc tgtctgaatg 1740 atcttgtgta agggtttggt tatggagtct tgtgccaaac ctactaggcc attagccctt 1800 caccatctac ctgcttggtc tttcattgct aagactaact caagataatc ctagagtctt 1860 aaagcatttc aggccagtgt ggtgtcttgc gcctgtactc ccagcacttt gggaggccga 1920 ggcaggtgga tcgcttgagc caggagtttt aagtccagct tggccaagat ggtgaaatcc 1980 catctctaca aaaaatgcag aacttaatct ggacacactg ttacacgtgc ctgtagtccc 2040 agctactcta tagcctgagg tgggagaatc acttaagcct ggaaggtgga agttgcagtg 2100 agtcgagatt gcactgctgc attccagcca gggtgacaga gtgagaccat gtttcaaaca 2160 agaaacattt cagagggcaa gtaaacagat ttgattgtga ggcttctaat aaagtagtta 2220 ttagtagtg 2229 15 7840 DNA Homo sapiens 15 atgacaactg aattaagttc atatgggtat ttgggatccg agaattctgc tttgttcaat 60 agagtctgca ccagttactg tgaagaagga gtagagtctg ctgccctctt gggatgtgac 120 aatagctcat ctactggaaa taccagtttc tcttcccttc tgagggatta ccctctgcat 180 cttttccata tgaaaacccc atttcctctt tcctttattg aatgcccctc aaaatcagaa 240 cttacatcat taggcattat tctctatttc cttgatgata tggaggatga gattttcaga 300 cactatgcag agctgaggcc acagaatttc ccctgttccg taagaaggaa caacagtgct 360 tttatgacat catctgattt tgcagaacga gcagccggtg tgtaccacag agaagcacgg 420 tctggcaaat acaagctcac ctacgcagaa gctaaggcgg tgtgtgaatt tgaaggcggc 480 catctcgcaa cttacaagca gctagaggca gccagaaaaa ttggatttca tgtctgtgct 540 gctggatgga tggctaaggg cagagttgga taccccattg tgaagccagg gcccaactgt 600 ggatttggaa aaactggcat tattgattat ggaatccgtc tcaataggag tgaaagatgg 660 gatgcctatt gctacaaccc acacgcaaag gagtgtggtg gcgtctttac agatccaaag 720 caaattttta aatctccagg cttcccaaat gagtacgaag ataaccaaat ctgctactgg 780 cacattagac tcaagtatgg tcagcgtatt cacctgagtt ttttagattt tgaccttgaa 840 gatgacccag gttgcttggc tgattatgtt gaaatatatg acagttacga tgatgtccat 900 ggctttgtgg gaagatactg tggagatgag cttccagatg acatcatcag tacaggaaat 960 gtcatgacct tgaagtttct aagtgatgct tcagtgacag ctggaggttt ccaaatcaaa 1020 tatgttgcaa tggatcctgt atccaaatcc agtcaaggaa aaaatacaaa agtcagaatg 1080 caacgagatc tggttgatac tgcacagaga tcagctccag ggcccagtgc aaggagaagg 1140 gtggccgaca tgacggccag gggtcagagc cccctcgcgc cgctgttgga gactttggaa 1200 gacccttctg cctcccatgg agggcagact gacgcttacc tgactctgac cagtcgtatg 1260 actggagaag aaggaaaaga agtaattaca gaaattgaga aaaaacttcc tcggctgtac 1320 aaagttttaa aggtatccag tataattgat tcattagaaa tactgtttaa caaaggagag 1380 acgcattctg ctgttgttga ttttgaagca ttaaatgtta tcgtaaggct aattgaacaa 1440 gccccaattc aaatgggaga agaggcagtg aggtgggcaa aactggtcat acctttagtg 1500 gttcattcag cacaaaaggt acatttgcgg ggagcaactg ctctggagat gggaatgcca 1560 ttattgcttc agaaacagca agaaatagca tctattacgg agcagcttat gactactacc 1620 ttgcatcgaa gtgggagttt catcaattct ctcttgcaac tagaagaact tggatttcgt 1680 agtggagcac ccatgattaa aaagatagct tttattgctt ggaagagttt aatagataat 1740 tttgctttaa atccagatat actatgtagt gcaaaaagac tcaagttgtt aatgcagcct 1800 ttgagttcca tccatgtgag aacagaaact ctagcattaa caaaactaga agtctggtgg 1860 tatttactga tgagacttgg acctcatctt cctgctaatt ttgaacaggt ttgtgtgcct 1920 ctgattcaaa gtacaataag cattgattct aatgcctcac ctcagggcaa ttcgtgtcat 1980 gtagctacat ctccaggttt aaatcctatg actcctgtac acaaaggtgc ttcctccccg 2040 tacggagccc cgggaactcc ccgaatgaac ctgagttcga atttaggtgg aatggccaca 2100 atcccatcca ttcaactttt gggacttgaa atgttgcttc atttcttgtt gggtccagaa 2160 gccttgagtt ttgctaagca aaataaactt gtgctgagct tagagccatt ggaacatccg 2220 ttaatcagca gcccttcctt tttttccaaa catgcaaata cacttatcac tgctgttcat 2280 gatagctttg ttgcagttgg aaaagatgcc cccggtaaca aaaaagagaa accaggttct 2340 gaagttttga ctctcttatt aaagtctttg gaaagcatag taaagtctga agtatttcct 2400 gtatcaaaaa cgctgggaac tccagctttg ttcttaattc aattaatttt caacaatttc 2460 ttggaatgtg gtgtatcaga tgaaaggttc tttctcagtt tggaatcact tgtaggctgt 2520 gttctttctg gtccaacttc accactagct ttcagtgact cagttttaaa tgttattaat 2580 caaaatgcaa agcagttgga aaataaggag catctctgga aaatgtggag tgttatagtc 2640 accccattaa ctgaattgat taatcagacc aatgaagtaa atcaaggtga tgccttagaa 2700 cataatttta gtgccatcta tggtgcattg actttaccag taaaccacat tttttcagaa 2760 cagagatttc cagtggccac catgaagact ttgcttagaa cttggtcaga attatataga 2820 gcatttgctc gttgtgctgc tttggtggca acagcagaag agaacttgtg ctgtgaggaa 2880 ctttcttcca agataatgtc cagtttggaa gatgaaggct tttctaattt gttgttcgtg 2940 gatagaatta tttatattat tactgtaatg gttgattgca ttgacttctc accatataat 3000 attaaatatc agcccaaagt taaatcacca cagagacctt cagattggtc caaaaagaag 3060 aatgagcccc tagggaaatt gacttcttta tttaaactta ttgtgaaagt gatctattct 3120 ttccacacac tgagcttcaa ggaagcacat tctgataccc tcttcactat tggcaactca 3180 atcaccggca ttatttccag tgtacttggg catatttctt tgccttctat gatccgaaaa 3240 atatttgcaa ctttaacaag acctctggca ttattttatg aaaactcaaa gcttgatgaa 3300 gttcctaaag tatatagttg tctgaacaac aagttagaaa agctactggg agaaattatt 3360 gcttgtctgc aattcagcta caccggaact tatgatagtg aacttcttga acaactctcc 3420 ccactattat gcataatatt tctgcacaag aataaacaga ttcgaaaaca gagtgctcag 3480 ttctggaatg ccacttttgc caaagtgatg atgttggttt atcctgaaga gttaaaacca 3540 gtactaacac aagccaaaca aaaatttctg ctcctgttgc ctggtttgga aactgttgaa 3600 atgatggagg aatccagtgg accatattct gatggactga aacttgaatc ttcgtcttta 3660 aaagtaaagg gtgaaattct tttggaagag gaaaagtcta ctgactttgt gtttatacct 3720 ccagaaggaa aagatgcaaa ggaaagaata ttaactgatc atcaaaaaga agttctcaaa 3780 acaaagcggt ttgaggagca aatggacagt gacattgtca ttcctcaaga tgtcacggaa 3840 gactgtggta tggctgaaca tcttgaaaag tcctcccttt cgaataatga gtgtggttct 3900 cttgacaaaa ccagtccaga aatgtcaaac agtaataatg atgaaagaaa aaaagcttta 3960 atttcatcaa ggaaaacatc aactgaatgt gcatctagta cagaaaattc tttcgttgtc 4020 agcagtagtt cagtttctaa taccactgtt gctggaactc ccccataccc tacaagtcgg 4080 aggcaaacct ttattacttt ggagaagttt gatggttcag aaaatagacc ttttagtcca 4140 tcccccttga ataatatttc atcaactgtt acagtgaaaa ataaccagga aaccatgatt 4200 aaaacagatt ttctaccaaa agcaaagcaa agagaaggga ctttttcaaa atctgattct 4260 gaaaaaatag tgaatggaac taagagatca agccggagag ctggtaaagc tgaacaaaca 4320 gggaataaaa ggtctaagcc cttaatgaga tctgagccgg agaaaaatac tgaggaatct 4380 gttgaaggca ttgtagtctt agaaaataac ccacctggtt tgcttaatca aacagaatgt 4440 gtgtcagata atcaggttca tctttctgaa tctacaatgg agcatgacaa tacaaagctt 4500 aaagcagcaa cagtggaaaa tgctgtatta ttggaaacta atactgtaga ggagaaaaat 4560 gtagaaatta atttggaatc caaagagaat acacccccag tagtaatatc agcagatcaa 4620 atggtaaatg aggatagtca ggttcagata actccaaatc agaaaaccct tagacggtct 4680 tcaaggcgac gttcagaagt agtagagtct accactgaaa gccaagataa ggaaaatagt 4740 catcaaaaaa aggaacgacg taaggaagaa gaaaaacctc ttcagaagag tccattgcat 4800 ataaaagatg atgtgttacc taaacaaaaa ctgattgctg aacaaactct acaggagaat 4860 ttaattgaga aaggaagtaa tttacatgag aagactcttg gggaaactag tgctaatgca 4920 gaaactgaac aaaataaaaa aaaggcagac cctgagaaca ttaagtctga gggggatggt 4980 acccaggaca ttgtagataa gtcctctgag aaactagtca gaggccgaac acggtatcaa 5040 actagaagag catctcaggg tttgctttcc agcattgaaa actcagaatc tgatagttcg 5100 gaggcaaaag aagaaggttc taggaagaag agatctggaa aatggaaaaa caaaagcaat 5160 gaaagtgttg acattcaaga tcaagaagag aaagtggtga aacaggaatg tataaaagct 5220 gaaaatcagt cacatgatta taaagcaact tctgaagaag atgtaagcat aaaatctccg 5280 atttgcgaaa aacaagatga aagtaatact gtaatatgtc aggattctac agtaacttca 5340 gatttgttgc aagttcctga tgatttacca aatgtgtgtg aggaaaaaaa tgaaactagc 5400 aaatatgcag aatattcctt tacaagtcta cctgtgccag aatcaaatct aaggactaga 5460 aatgccatta agagattaca taagcgagac tcttttgata attgtagttt gggagaatcc 5520 tcaaaaatag ggatatcaga tatttcttcg ctttcagaaa aaacttttca aacacttgaa 5580 tgccaacaca agagaagtag gagggtgagg agatctaaag gttgtgattg ctgtggggaa 5640 aaatcacaac ctcaggaaaa gtcactcatt gggttaaaga atacagaaaa taatgacgta 5700 gagattagtg aaacaaaaaa ggcagatgtg caagcacctg taagcccatc agaaacttct 5760 caagctaatc catattctga aggacaattt ttagatgaac atcatagtgt gaattttcat 5820 ttgggtctca aagaggataa tgatactatt aatgattcat taattgtttc tgaaaccaaa 5880 tcaaaagaaa acactatgca agaatctctt ccttctggaa tagtaaactt tagagaggaa 5940 atttgtgata tggattctag tgaagcaatg tctcttgaaa gccaggagtc acctaatgaa 6000 aattttaaaa ctgttggccc gtgtttagga gactcgaaaa atgtttcaca ggaatctttg 6060 gagacaaaag aagaaaaacc agaagaaacc ccaaaaatgg aactgagtct agagaatgtt 6120 actgttgaag gaaatgcatg taaagtaaca gaatccaatc tagagaaagc aaaaactatg 6180 gaattgaatg taggaaatga agctagcttt catggacaag agagaaccaa aactggtatt 6240 tctgaagaag cagcaataga agaaaataaa agaaatgatg actctgaagc agacacagct 6300 aaactgaatg ccaaagaagt agcaactgag gaatttaatt cagatattag tctttctgat 6360 aatactacac ctgtaaaatt gaatgctcaa actgagattt ctgaacaaac agcagctggg 6420 gaactagatg gaggaaatga tgtatctgat ctacactcat ctgaagaaac gaataccaaa 6480 atgaaaaata atgaagaaat gatgatcggc gaggcaatgg ctgaaactgg ccatgatggt 6540 gaaacagaga atgagggcat aactaccaaa acctcaaagc ctgatgaagc tgaaacaaac 6600 atgttgactg cagaaatgga caactttgtt tgtgacacag ttgaaatgag cactgaagaa 6660 ggaatcattg acgctaataa aactgaaaca aatactgagt atagtaaatc tgaagaaaaa 6720 ttagataaca atcaaatggt aatggaaagt gatattttac aggaagatca ccatacttca 6780 cagaaagtgg aggaaccatc acagtgtctg gcatctggaa cagctatctc tgagctaata 6840 atagaagaca ataatgcatc tcctcaaaaa ctaagggaac ttgatccttc acttgtgtca 6900 gcaaatgaca gtcctagtgg catgcagaca cgctgtgtct ggtctccttt ggcttctccg 6960 tctacgagca ttttaaagag aggactaaaa agatcccaag aagatgaaat ctcatcacct 7020 gttaataagg ttcgccgtgt ctcctttgca gatccaatat accaagcagg attggcagat 7080 gacattgata gacggtgctc tattgttagg tcccattctt ccaatagttc tcccatagga 7140 aaaagtgtta aaacttctcc tactacacaa tctaagtcag ttgacctctg tgtaacagct 7200 tctgaaattt attctaagat ttcagaaatg gccaaagaat ccataccatg cccaacagaa 7260 agtgtttacc caccattggt gaactgtgtg gcaccagttg acatcatttt acctcagatt 7320 acatcaaaca tgtgggcaag aggcctggga caactcatta gagctaagaa tataaaaact 7380 attggtgatt tgagtactct tacagcatct gaaataaaaa ctcttcctat ccgttctcca 7440 aaagtgtcca atgtaaaaaa ggctctcaga atatatcatg agcagcaggt gaagactcgt 7500 ggactagaag agattccagt ttttgatatt tctgaaaaaa cagtaaatgg aatagaaaat 7560 aaatctttgt cacctgatga agaaagactt gtctcagata taattgatcc tgttgcttta 7620 gaaattccat tatccaaaaa ccttctggca cagattagtg ctcttgctct tcagctggat 7680 tcagaagatc ttcataatta ttcaggaagc caactatttg aaatgcacga gaaactaagt 7740 tcagagggaa tatttttggc cacagtgtgc caatttataa ttgtagataa agctgaattt 7800 actgggcagc aagcttatat gctgatagaa gttgatgcac 7840 16 4023 DNA Homo sapiens 16 gcgtgggtca gctgatcgcg cactgagggt gcgatcccgg gctccccatt ccttcctggg 60 gcgcctcccc ggcccagggc caactgggtc ccggtgtcgg caggcctggg gtcggcgacg 120 gctgctcttt tcgttctgtc gcctgcccga tggacgagcc tcccgggaag cccctcagct 180 gtgaggagaa ggaaaagtta aaggagaaat tagcattctt gaaaagggaa tacagcaaga 240 cactagcccg ccttcagcgt gcccaaagag ctgaaaagat taagcattct attaagaaaa 300 cagtagaaga acaagattgt ttgtctcagc aggatctctc accgcagcta aaacactcag 360 aacctaaaaa taaaatatgt gtttatgaca agttacacat caaaacccat cttgatgaag 420 aaactggaga aaagacatct atcacacttg atgttgggcc tgagtccttt aaccctggag 480 atggcccagg aggattacct atacaaagaa cagatgacac ccaagaacat tttccccaca 540 gggtcagtga ccctagtggt gagcaaaagc agaagctgcc aagcagaaga aagaagcagc 600 agaagaggac atttatttca caggagagag actgtgtctt tggcactgat tcactcagat 660 tgtctgggaa aagactaaag gaacaggaag aaatcagtag caaaaatcct gctagatcac 720 cagtaactga aataagaact caccttttaa gtcttaaatc tgaacttcca gattctccag 780 aaccagttac agaaattaat gaagacagtg tattaattcc accaactgcc caaccagaaa 840 aaggtgttga tacattccta agaagaccta atttcaccag ggcgactaca gttcctttac 900 agactctatc agatagcggt agtagtcagc accttgaaca cattcctcct aaaggtagca 960 gtgaacttac tactcacgac ctaaaaaaca ttagatttac ttcacctgta agtttggagg 1020 cacaaggcaa aaaaatgact gtctctacag ataacctcct tgtaaataaa gctataagta 1080 aaagtggcca actgcccaca agttctaatt tagaggcaaa tatttcatgt tctctaaatg 1140 aactcaccta caataactta ccagcaaatg aaaaccaaaa cttaaaagaa caaaatcaaa 1200 cagagaaatc tttaaaatct cccagtgaca ctcttgatgg caggaatgaa aatcttcagg 1260 aaagtgagat tctaagtcaa cctaagagtc ttagcctgga agcaacctct cctctttctg 1320 cagaaaaaca ttcttgcaca gtgcctgaag gccttctgtt tcctgcagaa tattatgtta 1380 gaacaacacg aagcatgtcc aattgccaga ggaaagtagc cgtggaggct gtcattcaga 1440 gtcatttgga tgtcaagaaa aaagggttta aaaataaaaa taaggatgca agtaaaaatt 1500 taaacctttc caatgaggaa actgaccaaa gtgaaattag gatgtctggc acatgcacag 1560 gacaaccaag ttcaagaacc tctcagaaac ttctctcatt aactaaagtc agctctcccg 1620 ctgggcccac tgaagataat gacttgtcta ggaaggcagt tgcccaagca cctggtagaa 1680 gatacacagg aaaaagaaaa tcagcctgca ccccagcatc agatcattgt gaaccacttt 1740 tgccaacttc tagcctgtcg attgttaaca ggtccaagga agaagtcacc tcacacaaat 1800 atcagcacga aaaattattt attcaagtga aagggaagaa aagtcgtcat caaaaagagg 1860 attccctttc ttggagtaat agtgcttatt tatccttgga tgatgatgct ttcacggctc 1920 catttcatag ggatggaatg ctgagtttaa agcaactact gtcttttctc agtatcacag 1980 actttcagtt acctgatgaa gactttggac ctcttaagct tgaaaaagtg aagtcctgct 2040 cagaaaaacc agtggagccc tttgagtcaa aaatgtttgg agagagacat cttaaagagg 2100 gaagctgtat ttttccagag gaactgagtc ctaaacgcat ggatacagaa atggaggact 2160 tagaagagga ccttattgtt ctaccaggaa aatcacatcc caaaaggcca aactcgcaaa 2220 gccagcatac aaagacgggc ctttcttcat ccatattact ttatactcct ttaaatacgg 2280 ttgcgcctga tgataatgac aggcctacca cagacatgtg ttcacctgct ttccccatct 2340 taggtactac tccagccttt ggccctcaag gctcctatga aaaagcatct acagaagttg 2400 ctggacgaac ttgctgcaca ccccaacttg ctcatttgaa agactcagtc tgtcttgcca 2460 gtgatactaa acaattcgac agttcaggca gcccagcaaa accacatacc accctgcaag 2520 tgtcaggcag gcaaggacaa cctacctgtg actgtgactc tgtcccgcca ggaacacctc 2580 cacccattga gtcattcact tttaaagaaa atcagctctg tagaaacaca tgccaggagc 2640 tgcataaaca ttccgtcgaa cagactgaaa cagcagagct tcctgcttct gatagcataa 2700 acccaggcaa cctacaattg gtttcagagt taaagaatcc ttcaggttcc tgttccgtag 2760 atgtgagtgc catgttttgg gaaagagccg gttgtaaaga gccatgtatc ataactgctt 2820 gcgaagatgt agtttctctt tggaaagctc tggatgcttg gcagtgggaa aaactttata 2880 cctggcactt cgcagaggtt ccagtattac agatagttcc agtgcctgat gtgtataatc 2940 tcgtgtgtgt agctttggga aatttggaaa tcagagagat cagggcattg ttttgttcct 3000 ctgatgatga aagtgaaaag caagtactac tgaagtctgg aaatataaaa gctgtgcttg 3060 gcctgacaaa gaggaggcta gttagtagca gtgggaccct ttctgatcaa caagtagaag 3120 tcatgacgtt tgcagaagat ggaggaggca aagaaaacca atttttgatg ccccctgagg 3180 agactatact aacttttgct gaggtccaag ggatgcaaga agctctgctt ggtactacta 3240 ttatgaacaa cattgttatt tggaatttaa aaactggtca actcctgaaa aagatgcaca 3300 ttgatgattc ttaccaagct tcagtctgtc acaaagccta ttctgaaatg gggcttctct 3360 ttattgtcct gagtcatccc tgtgccaaag agagtgagtc gttgcgaagc cctgtgtttc 3420 agctcattgt gattaaccct aagacgactc tcagcgtggg tgtgatgctg tactgtcttc 3480 ctccagggca ggctggcagg ttcctggaag gtgacgtgaa agatcactgt gcagcagcaa 3540 tcttgacttc tggaacaatt gccatttggg acttacttct cggtcagtgt actgccctcc 3600 tcccacctgt ctctgaccaa cattggtctt ttgtgaaatg gtcgggtaca gactctcatt 3660 tgctggctgg acaaaaagat ggaaatatat ttgtatacca ctattcataa gttagggtaa 3720 agtgaaaaca caattttctg gatatattgg gcctcttagt attttttgga gttttaaata 3780 taaaggagaa tatctgaatg acacttaaaa tgattgcttg tttatgtcca gacagactta 3840 ttttttattc taatgatggt agcaccactg atcttggatg tacatttatg tatactttga 3900 gaaaaagggt tttaggttga tttttgtaat ttcccacatt tgtacatgtg cttttaaagg 3960 tgtacataaa gcttcaaatg gcaataaata tttattttta tacattcaaa aaaaaaaaaa 4020 aaa 4023 17 3911 DNA Homo sapiens 17 caggtgattg actggccagc tgcctgaagg agcgccaggt cctccttgct ggcaggtggc 60 gaagcccatt ggggcggcgg tgcagaccgc ggcggcggct gcggcggtct ggctcgggag 120 gcgttcctgg ggccaaggcc atggccccgc ggctgcagct ggagaaggcg gcctggcgct 180 gggcggagac ggtgcggccc gaggaggtgt cgcaggagca catcgagacc gcttaccgca 240 tctggctgga gccctgcatt cgcggcgtgt gcagacgaaa ctgcaaagga aatccgaatt 300 gcttggttgg tattggtgag catatttggt taggagaaat agatgaaaat agttttcata 360 acatcgatga tcccaactgt gagaggagaa aaaagaactc atttgtgggc ctgactaacc 420 ttggagccac ttgttatgtc aacacatttc ttcaagtgtg gtttctcaac ttggagcttc 480 ggcaggcact ctacttatgt ccaagcactt gtagtgacta catgctggga gacggcatcc 540 aagaagaaaa agattatgag cctcaaacaa tttgtgagca tctccagtac ttgtttgcct 600 tgttgcaaaa cagtaatagg cgatacattg atccatcagg atttgttaaa gccttgggcc 660 tggacactgg acaacagcag gatgctcaag aattttcaaa gctctttatg tctctattgg 720 aagatacttt gtctaaacaa aagaatccag atgtgcgcaa tattgttcaa cagcagttct 780 gtggagaata tgcctatgta actgtttgca accagtgtgg cagagagtct aagcttttgt 840 caaaatttta tgagctggag ttaaatatcc aaggccacaa acagttaaca gattgtatct 900 cggaattttt gaaggaagaa aaattagaag gagacaatcg ctatttttgc gagaactgtc 960 aaagcaaaca gaatgcaaca agaaagattc gacttcttag ccttccttgc actctgaact 1020 tgcagctaat gcgttttgtc tttgacaggc aaactggaca taagaaaaag ctgaatacct 1080 acattggctt ctcagaaatt ttggatatgg agccttatgt ggaacataaa ggtgggtcct 1140 acgtgtatga actcagcgca gtcctcatac acagaggagt gagtgcttat tctggccact 1200 acatcgccca cgtgaaagat ccacagtctg gtgaatggta taagtttaat gatgaagaca 1260 tagaaaagat ggaggggaag aaattacaac tagggattga ggaagatcta gcagaacctt 1320 ctaagtctca gacacgtaaa cccaagtgtg gcaaaggaac tcattgctct cgaaatgcat 1380 atatgttggt ttatagactg caaactcaag aaaagcccaa cactactgtt caagttccag 1440 cctttcttca agagctggta gatcgggata attccaaatt tgaggagtgg tgtattgaaa 1500 tggctgagat gcgtaagcaa agtgtggata aaggaaaagc aaaacacgaa gaggttaagg 1560 agctgtacca aaggttacct gctggagctg agccctatga gtttgtctct ctggaatggc 1620 tgcaaaagtg gttggatgaa tcaacaccta ccaaacctat tgataatcac gcttgcctgt 1680 gttcccatga caagcttcac ccggataaaa tatcaattat gaagaggata tctgaatatg 1740 cagctgacat tttctatagt agatatggag gaggtccaag actaactgtg aaagccctgt 1800 gtaaggaatg tgtagtagaa cgttgtcgca tattgcgtct gaagaaccaa ctaaatgaag 1860 attataaaac tgttaataat ctgctgaaag cagcagtaaa gggcgatgga ttttgggtgg 1920 ggaagtcctc cttgcggagt tggcgccagc tagctcttga acagctggat gagcaagatg 1980 gtgatgcaga acaaagcaac ggaaagatga acggtagcac cttaaataaa gatgaatcaa 2040 aggaagaaag aaaagaagag gaggaattaa attttaatga agatattctg tgtccacatg 2100 gtgagttatg catatctgaa aatgaaagaa ggcttgtttc taaagaggct tggagcaaac 2160 tgcagcagta ctttccaaag gctcctgagt ttccaagtta caaagagtgc tgttcacagt 2220 gcaagatttt agaaagagaa ggggaagaaa atgaagcctt acataagatg attgcaaacg 2280 agcaaaagac ttctctccca aatttgttcc aggataaaaa cagaccgtgt ctcagtaact 2340 ggccagagga tacggatgtc ctctacatcg tgtctcagtt ctttgtagaa gagtggcgga 2400 aatttgttag aaagcctaca agatgcagcc ctgtgtcatc agttgggaac agtgctcttt 2460 tgtgtcccca cgggggcctc atgtttacat ttgcttccat gaccaaagaa gattctaaac 2520 ttatagctct catatggccc agtgagtggc aaatgataca aaagctcttt gttgtggatc 2580 atgtaattaa aatcacgaga attgaagtgg gagatgtaaa cccttcagaa acacagtata 2640 tttctgagcc caaactctgt ccagaatgca gagaaggctt attgtgtcag cagcagaggg 2700 acctgcgtga atacactcaa gccaccatct atgtccataa agttgtggat aataaaaagg 2760 tgatgaagga ttcggctccg gaactgaatg tgagtagttc tgaaacagag gaggacaagg 2820 aagaagctaa accagatgga gaaaaagatc cagattttaa tcaaatcatg catgcatttt 2880 cagttgctcc ttttgaccag aatttgtcaa ttgatggaaa gattttaagt gatgactgtg 2940 ccaccctagg cacccttggc gtcattcctg aatctgtcat tttattgaag gctgatgaac 3000 caattgcaga ttatgctgca atggatgatg tcatgcaagt ttgtatgcca gaagaagggt 3060 ttaaaggtac tggtcttctt ggacattaat ctttgaatac ttgctgactg ctaagaaatg 3120 accagagggg aagaggagtt tgacatgtta gggcattaaa gcaaaggtgg atttaagaat 3180 taaaccatta catgcccctt ccaaaaggca gaaatccatt caaacgtgac tgtcccaaat 3240 gccttatgtc aaataaagca gattgcactg atggacatca gacttgaagg aaatgtttcc 3300 aattttatat ttaagggggg tggtgggtgg gagggggcaa gtaaagacgg aacaagttta 3360 gtagcagtaa tagtaaatca tgtttacata tgagatttat agtcgtggga ggggaataaa 3420 gttctgttat atttccttgc tcgagtttca taccagatgc gttggtccat aaaggattgt 3480 atcaagtaga tgggacaaca ttctgctctg aacgaaaagt aattttagag acataacctg 3540 cttaccaatg cctgtctttg attcatattc tactttcaat aaagcatgaa agtgaagaac 3600 ttgtcctaag tgtggaaaag tgtcttcaga tttagactct tctccatgtc agctgcagcg 3660 ccacccgcct tacacctgcc cggccgtctg tctcttggta ttgggtaaag gagggggcac 3720 ctgcatgtct cctgcaatga gcaaggaatt atgtctcatg ttttgacttc agaggctttt 3780 tgctttggtg catttcagaa aggatggaga acatttatta tgtgtgaaag catcctcttc 3840 cggttttgct gttattcaaa agtgggaaat gtacctggca cgtttgaaaa taaaaaatct 3900 gactacctat c 3911 18 3682 DNA Homo sapiens 18 aaaactgcga ctgcgcggcg tgagctcgct gagacttcct ggaccccgca ccaggctgtg 60 gggtttctca gataactggg cccctgcgct caggaggcct tcaccctctg ctctgggtaa 120 agttcattgg aacagaaaga aatggattta tctgctcttc gcgttgaaga agtacaaaat 180 gtcattaatg ctatgcagaa aatcttagag tgtcccatct gtctggagtt gatcaaggaa 240 cctgtctcca caaagtgtga ccacatattt tgcaaatttt gcatgctgaa acttctcaac 300 cagaagaaag ggccttcaca gtgtccttta tgtaagaatg atataaccaa aaggagccta 360 caagaaagta cgagatttag tcaacttgtt gaagagctat tgaaaatcat ttgtgctttt 420 cagcttgaca caggtttgga gtatgcaaac agctataatt ttgcaaaaaa ggaaaataac 480 tctcctgaac atctaaaaga tgaagtttct atcatccaaa gtatgggcta cagaaaccgt 540 gccaaaagac ttctacagag tgaacccgaa aatccttcct tgcaggaaac cagtctcagt 600 gtccaactct ctaaccttgg aactgtgaga actctgagga caaagcagcg gatacaacct 660 caaaagacgt ctgtctacat tgaattggga tctgattctt ctgaagatac cgttaataag 720 gcaacttatt gcagtgtggg agatcaagaa ttgttacaaa tcacccctca aggaaccagg 780 gatgaaatca gtttggattc tgcaaaaaag ggtgaagcag catctgggtg tgagagtgaa 840 acaagcgtct ctgaagactg ctcagggcta tcctctcaga gtgacatttt aaccactcag 900 cagagggata ccatgcaaca taacctgata aagctccagc aggaaatggc tgaactagaa 960 gctgtgttag aacagcatgg gagccagcct tctaacagct acccttccat cataagtgac 1020 tcttctgccc ttgaggacct gcgaaatcca gaacaaagca catcagaaaa agcagtatta 1080 acttcacaga aaagtagtga ataccctata agccagaatc cagaaggcct ttctgctgac 1140 aagtttgagg tgtctgcaga tagttctacc agtaaaaata aagaaccagg agtggaaagg 1200 tcatcccctt ctaaatgccc atcattagat gataggtggt acatgcacag ttgctctggg 1260 agtcttcaga atagaaacta cccatctcaa gaggagctca ttaaggttgt tgatgtggag 1320 gagcaacagc tggaagagtc tgggccacac gatttgacgg aaacatctta cttgccaagg 1380 caagatctag agggaacccc ttacctggaa tctggaatca gcctcttctc tgatgaccct 1440 gaatctgatc cttctgaaga cagagcccca gagtcagctc gtgttggcaa cataccatct 1500 tcaacctctg cattgaaagt tccccaattg aaagttgcag aatctgccca gagtccagct 1560 gctgctcata ctactgatac tgctgggtat aatgcaatgg aagaaagtgt gagcagggag 1620 aagccagaat tgacagcttc aacagaaagg gtcaacaaaa gaatgtccat ggtggtgtct 1680 ggcctgaccc cagaagaatt tatgctcgtg tacaagtttg ccagaaaaca ccacatcact 1740 ttaactaatc taattactga agagactact catgttgtta tgaaaacaga tgctgagttt 1800 gtgtgtgaac ggacactgaa atattttcta ggaattgcgg gaggaaaatg ggtagttagc 1860 tatttctggg tgacccagtc tattaaagaa agaaaaatgc tgaatgagca tgattttgaa 1920 gtcagaggag atgtggtcaa tggaagaaac caccaaggtc caaagcgagc aagagaatcc 1980 caggacagaa agatcttcag ggggctagaa atctgttgct atgggccctt caccaacatg 2040 cccacagatc aactggaatg gatggtacag ctgtgtggtg cttctgtggt gaaggagctt 2100 tcatcattca cccttggcac aggtgtccac ccaattgtgg ttgtgcagcc agatgcctgg 2160 acagaggaca atggcttcca tgcaattggg cagatgtgtg aggcacctgt ggtgacccga 2220 gagtgggtgt tggacagtgt agcactctac cagtgccagg agctggacac ctacctgata 2280 ccccagatcc cccacagcca ctactgactg cagccagcca caggtacaga gccacaggac 2340 ccaagaatga gcttacaaag tggcctttcc aggccctggg agctcctctc actcttcagt 2400 ccttctactg tcctggctac taaatatttt atgtacatca gcctgaaaag gacttctggc 2460 tatgcaaggg tcccttaaag attttctgct tgaagtctcc cttggaaatc tgccatgagc 2520 acaaaattat ggtaattttt cacctgagaa gattttaaaa ccatttaaac gccaccaatt 2580 gagcaagatg ctgattcatt atttatcagc cctattcttt ctattcaggc tgttgttggc 2640 ttagggctgg aagcacagag tggcttggcc tcaagagaat agctggtttc cctaagttta 2700 cttctctaaa accctgtgtt cacaaaggca gagagtcaga cccttcaatg gaaggagagt 2760 gcttgggatc gattatgtga cttaaagtca gaatagtcct tgggcagttc tcaaatgttg 2820 gagtggaaca ttggggagga aattctgagg caggtattag aaatgaaaag gaaacttgaa 2880 acctgggcat ggtggctcac gcctgtaatc ccagcacttt gggaggccaa ggtgggcaga 2940 tcactggagg tcaggagttc gaaaccagcc tggccaacat ggtgaaaccc catctctact 3000 aaaaatacag aaattagccg gtcatggtgg tggacacctg taatcccagc tactcaggtg 3060 gctaaggcag gagaatcact tcagcccggg aggtggaggt tgcagtgagc caagatcata 3120 ccacggcact ccagcctggg tgacagtgag actgtggctc aaaaaaaaaa aaaaaaaagg 3180 aaaatgaaac taggaaaggt ttcttaaagt ctgagatata tttgctagat ttctaaagaa 3240 tgtgttctaa aacagcagaa gattttcaag aaccggtttc caaagacagt cttctaattc 3300 ctcattagta ataagtaaaa tgtttattgt tgtagctctg gtatataatc cattcctctt 3360 aaaatataag acctctggca tgaatatttc atatctataa aatgacagat cccaccagga 3420 aggaagctgt tgctttcttt gaggtgattt ttttcctttg ctccctgttg ctgaaaccat 3480 acagcttcat aaataatttt gcttgctgaa ggaagaaaaa gtgtttttca taaacccatt 3540 atccaggact gtttatagct gttggaagga ctaggtcttc cctagccccc ccagtgtgca 3600 agggcagtga agacttgatt gtacaaaata cgttttgtaa atgttgtgct gttaacactg 3660 caaataaact tggtagcaaa ca 3682 19 2516 DNA Homo sapiens 19 cggacgcgcg cgcccctccc cctccccccg cgctcccaac gtgtggcggc tcgcgacccc 60 cggcaacccg gagaaggtct acagagcggc ctgcgccacg aacaaaagga tgccacggag 120 aaagaaaaaa gttaaagaag tctccgaatc tcggaacctg gagaagaagg atgtggaaac 180 taccagttct gtcagtgtga agaggaagcg tagacttgag gatgcattca ttgtgatatc 240 cgatagtgat ggagaggaac caaaggagga aaatgggttg cagaaaacga agacaaaaca 300 gtcgaataga gcaaagtgtt tggccaaaag aaaaatcgca cagatgacag aagaagaaca 360 gtttgctctg gctctcaaaa tgagtgagca ggaagctagg gaggtgaaca gccaggagga 420 ggaagaagag gagctcttga ggaaagccat tgctgaaagc ctgaatagtt gccggccttc 480 tgatgcttcc gctaccagat ctcgacctct ggccactgga ccgtcttccc agtcccatca 540 agagaaaacc acagactctg ggctcactga aggcatatgg cagctggtac ctccatcact 600 gtttaaaggc tcacatatca gtcagggaaa cgaggctgag gaaagagagg agccttggga 660 ccacactgaa aaaactgaag aggagccggt ctctggcagc tcaggaagct gggaccagtc 720 aagccagcca gtgtttgaga atgtgaacgt taaatctttt gacagatgta ctggccactc 780 ggctgagcac acacagtgtg ggaagccaca ggaaagtact gggaggggtt ctgcctttct 840 caaagctgtc cagggtagcg gggacacatc taggcactgt ctacctaccc tagcagatgc 900 caaaggtctc caggacactg ggggcactgt gaactatttc tggggtattc cattctgccc 960 tgatggagta gaccctaacc agtataccaa ggtcattctc tgccagttgg aggtttatca 1020 aaagagcctg aaaatggctc agaggcagct ccttaataaa aaaggttttg gggaaccagt 1080 gttacctaga cctccttctc tgatccagaa tgaatgtggc caaggagagc aggctagtga 1140 gaaaaatgga tgcatctcag aagatatggg agatgaagac aaagaggaga ggcaggagtc 1200 tagggcatct gactggcact caaaaaccaa ggatttccag gaaagctcaa ttaaaagctt 1260 gaaagagaaa cttttgttgg aggaagaacc aacaaccagt catggtcagt cttcccaagg 1320 gattgttgaa gaaacttctg aagagggaaa ctctgtacct gcttcacaaa gtgttgctgc 1380 tttgaccagt aagagaagct tagtccttat gccagagagt tctgcagaag aaatcactgt 1440 ttgtcctgag acccagctaa gttcctctga aacttttgac cttgaaagag aagtctctcc 1500 aggtagcaga gatatcttgg atggagtcag aataataatg gcagataagg aggttggtaa 1560 caaggaagat gctgagaagg aagtagctat ttctaccttc tcatccagta accaggtatc 1620 ctgcccgcta tgtgaccaat gctttccacc tacaaagatt ggacgacatg ccatgtactg 1680 caatggtctg atggaggaag atacagtatt gactcggaga caaaaagagg ccaagaccaa 1740 gagtgacagt gggacagctg cccagacttc tctagacatt gacaagaatg agaagtgtta 1800 cctctgtaaa tccctggtcc catttagaga gtatcagtgt catgtggact cctgtctcca 1860 gcttgcaaag gctgaccaag gagatggacc tgaagggagt ggaagagcat gttcaactgt 1920 ggaggggaag tggcagcaga ggctgaagaa cccaaaggaa aaaggccaca gtgaaggccg 1980 actccttagt ttcttggaac agtctgagca caagacttca gatgcagaca tcaagtcttc 2040 agaaacagga gccttcaggg tgccttcacc agggatggaa gaggcaggct gcagcagaga 2100 gatgcagagt tctttcacac gtcgtgactt aaatgaatct cccgtcaagt cttttgtttc 2160 catttcagaa gccacagatt gcttagtgga ctttaaaaag caagttactg tccagccagg 2220 tagtcggaca cggaccaaag ctggcagagg aagaaggaga aaattctgaa tttctagggt 2280 ccaaaagttg acaaaaccat tagtaggagg ggtgggccat gttctataag ccatagtggt 2340 ccctagttca ttgttgagca agtttttagc cctgcagttt tcaccaccag caccaccagc 2400 acctacccag cattctggtt tttatgtttt ttatgatcta tgcagacaac tgtgtattct 2460 gttttataac agtttgtttg aatttactta cagttaaaaa atttaaatat aaaaaa 2516 20 1865 DNA Homo sapiens 20 gagtgcgcac gcatcctgcc cgcggcgcgc gcgcaggtcg gtgcgtctgt cgggggcgcg 60 ctcgggtacc tgtaccccac gtagtcgccg gttaccgatc ggactaagtt ccagtggtga 120 tttacaagtc aagttaaaat gtccccagaa gtggccttga accgaatatc tccaatgctc 180 tcccctttca tatctagcgt ggtccggaat ggaaaagtgg gactggatgc tacaaactgt 240 ttgaggataa ctgacttaaa atctggctgc acatcattga ctcctgggcc caactgtgac 300 cgatttaaac tgcacatacc atatgctgga gagacattaa agtgggatat cattttcaat 360 gcccaatacc cagaactgcc tcccgatttt atctttggag aagatgctga attcctgcca 420 gacccctcag ctttgcagaa tcttgcctcc tggaatcctt caaatcctga atgtctctta 480 cttgtggtga aggaacttgt gcaacaatat caccaattcc aatgtagccg cctccgggag 540 agctcccgcc tcatgtttga ataccagaca ttactggagg agccacagta tggagagaac 600 atggaaattt atgctgggaa aaaaaacaac tggactggtg aattttcagc tcgtttcctt 660 ttgaagctgc ccgtagattt cagcaatatc cccacatacc ttctcaagga tgtaaatgaa 720 gaccctggag aagatgtggc cctcctctct gttagttttg aggacactga agccacccag 780 gtgtacccca agctgtactt gtcacctcga attgagcatg cacttggagg ctcctcagct 840 cttcatatcc cagcttttcc aggaggagga tgtctcattg attacgttcc tcaagtatgc 900 cacctgctca ccaacaaggt gcagtacgtg attcaagggt atcacaaaag aagagagtat 960 attgctgctt ttctcagtca ctttggcaca ggtgtcgtgg aatatgatgc agaaggcttt 1020 acaaaactca ctctgctgct gatgtggaaa gatttttgtt ttcttgtaca cattgacctg 1080 cctctgtttt tccctcgaga ccagccaact ctcacatttc agtccgttta tcactttacc 1140 aacagtggac agctttactc ccaggcccaa aaaaattatc cgtacagccc cagatgggat 1200 ggaaatgaaa tggccaaaag agcaaaggga tgccagggga gcagagatgc ctgcagcccg 1260 tgggagcaag tcctggcctt tgcagttgca aaaactggct gcaagctgct ccagccccag 1320 aggaactggc caagctccag agggcctcct tggagggcct cagagggaga gagaactgct 1380 cagtaatttt gatcactttg ggcttatttc aaaacctttg tccctcagtt ccaggaggca 1440 gcatttgcca atggaaagct ctaggaaaca ccagtcttga gaggtggcca gccagactgc 1500 ctgtccacat gcgtgtcagc acatacagcc gcttcctgga agccgcctgg aatgtcttca 1560 cggcagcgtt ttgctcacac agcagctttt gcacgcccca ggcagccccg actgctgaaa 1620 tccaacttga gctggctggt ggtccctgga tcctagagcc cttcacttcg ggttactccc 1680 tctttcttgc ctctatttct tagttggaag aaataaactc acaaattatg gtgcagtaat 1740 tttccgggga aagtaaagcc tcaggaatgc ccacgccttt cttccaaagc ctttgtctct 1800 gagacctctt aagttctaag attaaatgcc cctcgctgtt tctcctctga aaaaaaaaaa 1860 aaaaa 1865 21 2407 DNA Homo sapiens 21 gccaagatgg cggtgcaggt ggtgcaggcg gtgcaggcgg ttcatctcga gtctgacgct 60 ttcctcgttt gtctcaacca cgctctgagc acagagaagg aggaagtaat ggggctgtgc 120 ataggggagt tgaacgatga tacaaggagt gactccaaat ttgcatatac tggaactgaa 180 atgcgcacag ttgctgaaaa ggttgatgcc gtcagaattg ttcacattca ttctgtcatc 240 atcttacgac gttctgataa gaggaaggac cgagtagaaa tttctccaga gcagctgtct 300 gcagcttcaa cagaggcaga gaggttggct gaactgacag gccgccccat gagagttgtg 360 ggctggtatc attcccatcc tcatataact gtttggcctt cacatgttga tgttcgcaca 420 caagccatgt accagatgat ggatcaaggc tttgtaggac ttattttttc ctgtttcata 480 gaagataaga acacaaagac tggccgggta ctctacactt gcttccaatc catacaggcc 540 caaaagagtt cagagtatga gagaatcgaa atcccaatcc atattgtacc tcatgtcact 600 atcgggaaag tgtgccttga atcagcagta gagctgccca agatcctgtg ccaggaggag 660 caggatgcgt ataggaggat ccacagcctt acacatctgg actcagtaac caagatccat 720 aatggctcag tgtttaccaa gaatctgtgc agtcagatgt cggcagtcag cgggcctctc 780 ctacagtggt tggaggacag actggagcaa aaccaacagc atttgcagga attacaacaa 840 gaaaaggaag agcttatgca agaactttct tctctagaat aaatcaggag acaaaatggg 900 gaaagatgaa aatatccagt gtaaagttac ttaagctaaa tcaatttcaa agaagaaaaa 960 cttggaggac tcattttacc tgacttcaag acttactata aagctatagt aatcaagata 1020 gatggtattg gcagaggaac agacacatac gtcaatggaa cagatgagag aacccagaaa 1080 taaacccata taaatatgct cagctgattt tgaaaaagtg aaaaagcaat tcaatggagg 1140 aagaatagcc tttctgacaa attatgctag agcaattaga cacccatggc gaggagaaaa 1200 aagaacctct acttaaacct cacatcttat ataaaattta actcaaaatg tataacggac 1260 ttaaatgtga tacataaaac tagataactt tgaaaaaagc cacaggagaa aaatcttcag 1320 gatcttgggc taggtgacaa gttcttggac tttgccccga aagcacatcc ataaaagaca 1380 aaatctgata tattggactt cttcaaaatt taaaaacttg tgatttaaga agaggaaaag 1440 ataagctaca gattgagatg aatttgcaaa ccatatatct gatcaatttg gaatatataa 1500 agtgtactaa aaactcaact gaagtcaggc atggtagctc atgcttgtaa tctcaccact 1560 ttgggaggcc aagatgggag gagtgcttga ggttaggcgt tccagaccag cctgggcaac 1620 atagtgagac tcttgtctct acaaaaagtt tttttaaaaa attaactggg caccatgaca 1680 cacaccagta gtcccagcta ctagggaggc aggaggatca cttgagccca ggagtttgag 1740 gcctgcggtg agctgtgatc acaccaccac actccaacct gtgtaacaga gtgaggcctc 1800 atctcaaaaa aaaaaaaaag gccacaaaac tcaacaataa aaacaaacag tccaattaga 1860 aaatgggcaa aagacatgaa tagatgtttc actgaagagg atctatagat ggcaagtaag 1920 catatgaaaa gctgttaaac tccataagtc atcagggaat gcaaattgaa accacagcga 1980 ggctatgact tacttatctc aatggctaaa gaaaaaatag tgaaaatacc aaatactgat 2040 gaggatacaa actggatatt ttatacattg ctgacaggaa tgtaaaatgg tacagccact 2100 ctgggaaaga gtttatgaat ttcttatcaa gttaaacata attttttaat caagttaaac 2160 ataagaccca gcagttgtgc tcctggacat tcattccaga gaaatgaaaa cctatattgt 2220 acttgtactc aaatattcat aggagcttta tttgtaatag ccccaaactg gaaacaaccc 2280 agatgtccta caacaggtac atggttaaac aaaccatcca taacttggaa tactgctctg 2340 gaatgaaaag gaactaactg ttgatacaag aacttggttg tacctcaggg gtattatggt 2400 gaacaaa 2407 22 2530 DNA Homo sapiens 22 cagcttccct gtggtttccc gaggcttcct tgcttcccgc tctgcgagga gcctttcatc 60 cgaaggcggg acgatgccgg ataatcggca gccgaggaac cggcagccga ggatccgctc 120 cgggaacgag cctcgttccg cgcccgccat ggaaccggat ggtcgcggtg cctgggccca 180 cagtcgcgcc gcgctcgacc gcctggagaa gctgctgcgc tgctcgcgtt gtactaacat 240 tctgagagag cctgtgtgtt taggaggatg tgagcacatc ttctgtagta attgtgtaag 300 tgactgcatt ggaactggat gtccagtgtg ttacaccccg gcctggatac aagacttgaa 360 gataaataga caactggaca gcatgattca actttgtagt aagcttcgaa atttgctaca 420 tgacaatgag ctgtcagatt tgaaagaaga taaacctagg aaaagtttgt ttaatgatgc 480 aggaaacaag aagaattcaa ttaaaatgtg gtttagccct cgaagtaaga aagtcagata 540 tgttgtgagt aaagcttcag tgcaaaccca gcctgcaata aaaaaagatg caagtgctca 600 gcaagactca tatgaatttg tttccccaag tcctcctgca gatgtttctg agagggctaa 660 aaaggcttct gcaagatctg gaaaaaagca aaaaaagaaa actttagctg aaatcaacca 720 aaaatggaat ttagaggcag aaaaagaaga tggtgaattt gactccaaag aggaatctaa 780 gcaaaagctg gtatccttct gtagccaacc atctgttatc tccagtcctc agataaatgg 840 tgaaatagac ttactagcaa gtggctcctt gacagaatct gaatgttttg gaagtttaac 900 tgaagtctct ttaccattgg ctgagcaaat agagtctcca gacactaaga gcaggaatga 960 agtagtgact cctgagaagg tctgcaaaaa ttatcttaca tctaagaaat ctttgccatt 1020 agaaaataat ggaaaacgtg gccatcacaa tagactttcc agtcccattt ctaagagatg 1080 tagaaccagc attctgagca ccagtggaga ttttgttaag caaaccgtgc cctcagaaaa 1140 tataccattg cctgaatgtt cttcaccacc ttcatgcaaa cgtaaagttg gtggtacatc 1200 agggaggaaa aacagtaaca tgtccgatga attcattagt ctttcaccag gtacaccacc 1260 ttctacatta agtagttcaa gttacaggca agtgatgtct agtccctcag caatgaagct 1320 gttgcccaat atggctgtga aaagaaatca tagaggagag actttgctcc atattgcttc 1380 tattaagggc gacatacctt ctgttgaata ccttttacaa aatggaagtg atccaaatgt 1440 taaagaccat gctggatgga caccattgca tgaagcttgc aatcatgggc acctgaaggt 1500 agtggaatta ttgctccagc ataaggcatt ggtgaacacc accgggtatc aaaatgactc 1560 accacttcac gatgcagcca agaatgggca cgtggatata gtcaagctgt tactttccta 1620 tggagcctcc agaaatgctg ttaatatatt tggtctgcgg cctgtcgatt atacagatga 1680 tgaaagtatg aaatcgctat tgctgctacc agagaagaat gaatcatcct cagctagcca 1740 ctgctcagta atgaacactg ggcagcgtag ggatggacct cttgtactta taggcagtgg 1800 gctgtcttca gaacaacaga aaatgctcag tgagcttgca gtaattctta aggctaaaaa 1860 atatactgag tttgacagta cagtaactca tgttgttgtt cctggtgatg cagttcaaag 1920 taccttgaag tgtatgcttg ggattctcaa tggatgctgg attctaaaat ttgaatgggt 1980 aaaagcatgt ctacgaagaa aagtatgtga acaggaagaa aagtatgaaa ttcctgaagg 2040 tccacgcaga agcaggctca acagagaaca gctgttgcca aagctgtttg atggatgcta 2100 cttctatttg tggggaacct tcaaacacca tccaaaggac aaccttatta agctcgtcac 2160 tgcaggtggg ggccagatcc tcagtagaaa gcccaagcca gacagtgacg tgactcagac 2220 catcaataca gtcgcatacc atgcgagacc cgattctgat cagcgcttct gcacacagta 2280 tatcatctat gaagatttgt gtaattatca cccagagagg gttcggcagg gcaaagtctg 2340 gaaggctcct tcgagctggt ttatagactg tgtgatgtcc tttgagttgc ttcctcttga 2400 cagctgaata ttataccaga tgaacatttc aaattgaatt tgcacggttt gtgagagccc 2460 agtcattgta ctgtttttaa tgttcacatt tttacaaata ggtagagtca ttcatatttg 2520 tctttgaatc 2530 23 21 RNA Artificial Sequence siRNA oligonucleotide 23 aacuuaggug aagcagcauc u 21 24 21 RNA Artificial Sequence siRNA oligonucleotide 24 aagaggaagg accgaguaga a 21 25 21 RNA Artificial Sequence siRNA oligonucleotide 25 aaggugcagu acgugauuca a 21 26 21 RNA Artificial Sequence siRNA oligonucleotide 26 aaguuacuca gccaagaacg a 21 

What is claimed is:
 1. A method for modulating the activity of at least one component of a BRCA1-BRCA2-containing complex (BRCC) comprising contacting a BRCC or cell containing a BRCC with an agent that interacts with a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, so that the expression or activity of BRCC36 or BRE is altered thereby modulating an activity of at least one component of a BRCC.
 2. The method of claim 1 wherein the at least one component of a BRCC comprises BRCA2, BRCA1, RAD51, BARD1, BRCC300, BRCC140, BRCC130, BRCA1 Δ11, BRCC80, BRE, or BRCC36.
 3. The method of claim 1 wherein the activity of the component comprises ubiquitin E3 ligase activity, ubiquitin hydrolase activity, DNA repair activity, or transcriptional regulator activity.
 4. A method for identifying an agent that modulates the ubiquitin E3 ligase activity or ubiquitin hydrolase activity of BRCC comprising contacting BRCC with a test agent and monitoring the ability of said agent to alter the level of ubiquitination of select protein which is indicative of ubiquitin E3 ligase activity or ubiquitin hydrolase activity of BRCC.
 5. A method for identifying an agent that modulates the DNA repair activity of BRCC comprising contacting a cell containing BRCC with a test agent and monitoring the ability of said agent to alter cell survival rates in the presence of ionizing radiation or alter homology-directed DNA repair which is indicative of DNA repair activity of BRCC.
 6. A method for identifying an agent that modulates the transcriptional regulator activity of BRCC comprising contacting a cell containing BRCC with a test agent and monitoring the ability of said agent to alter the expression of genes containing p53 response elements which is indicative of transcriptional regulator activity of BRCC.
 7. An agent identified by the method of claim
 4. 8. An agent identified by the method of claim
 5. 9. An agent identified by the method of claim
 6. 10. A method for treating a cancer associated with BRCC comprising administering to a patient having a cancer associated with BRCC an effective amount of an agent identified by the method of claim
 4. 11. A method for treating a cancer associated with BRCC comprising administering to a patient having a cancer associated with BRCC an effective amount of an agent identified by the method of claim
 5. 12. A method for treating a cancer associated with BRCC comprising administering to a patient having a cancer associated with BRCC an effective amount of an agent identified by the method of claim
 6. 13. A method for identifying an agent that inhibits the expression of BRCC36 or BRE protein comprising contacting a cell expressing BRCC36 or BRE protein with a test agent and monitoring the ability of said agent to alter the expression of BRCC36 or BRE protein.
 14. An agent identified by the method of claim
 13. 15. A method for treating a cancer associated with BRCC comprising administering to a patient having a cancer associated with BRCC an effective amount of an agent of claim
 14. 16. An antibody which specifically recognizes BRCC36 or BRE protein.
 17. A method for diagnosing a cancer or the risk of developing a cancer associated with BRCC comprising detecting a level or sequence of a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, in sample; comparing said level or sequence of a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof in the sample to a level or sequence of a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, in a control; wherein a change in the level or sequence of a nucleic acid sequence encoding BRCC36 or BRE, or a product thereof, in the sample as compared to the control is indicative of a cancer or the risk of developing a cancer associated with BRCC. 